Structure of insulin in complex with n- and c-terminal regions of the insulin receptor alpha-chain

ABSTRACT

The present invention relates to the crystal structure of the insulin receptor ectodomain in complex with human insulin and to methods of using the crystal and related structural information to identify, design and screen for compounds that interact with or modulate the insulin receptor and insulin receptor signalling.

TECHNICAL FIELD

The present invention relates generally to structural studies of insulin binding to the insulin receptor (“IR”). In particular, the present invention relates to the crystal structure of insulin in complex with N- and C-terminal regions of the IR α-chain, and to methods of using the crystal structure and related structural information to identify, design and/or screen for agonists and antagonists that interact with and/or modulate the function of the IR.

BACKGROUND ART

The insulin receptor (“IR”), and its homologue the type 1 insulin-like growth factor receptor (“IGF-1R”), are closely related members of the tyrosine kinase receptor family, and are large, transmembrane, glycoprotein dimers consisting of several structural domains.

Insulin, a hormone produced by the pancreas, interacts with the IR, and via the IR signals into a complex network that ultimately controls the fundamental cellular processes of cell growth and differentiation, protein synthesis, as well as glucose uptake, synthesis and homeostasis (Cohen, 2006; Taniguchi et al., 2006). Insulin signalling also plays a role in neuronal development (Chiu and Cline, 2010). Insulin's role in the treatment of diabetes has underpinned decades of research into the biochemical and biophysical properties of the hormone (Ward and Lawrence, 2011). More recently, aberrant insulin receptor signalling has become implicated in cancer, in part due to its overlap with the closely-related insulin-like growth factor (“IGF”) signalling system and to an increased number of insulin receptors on cancer cells providing a mechanism for increased glucose uptake (Pollak, 2012). Brain insulin resistance is increasingly being seen as a potential causal factor in Alzheimer's disease (Talbot et al., 2012).

Despite these fundamental biological roles of insulin and the role of insulin signalling system in major diseases, there is to date no three-dimensional description of the way in which insulin interacts with the IR.

IR exists as two splice variant isoforms, IR-A and IR-B, which respectively lack or contain the 12 amino acids coded by exon 11. The longer variant, IR-B, is the isoform responsible for signalling metabolic responses. In contrast, IR-A signals predominantly mitogenic responses and is the preferentially expressed isoform in several cancers (Denley et al., 2003). Also, IR-A is capable of binding insulin-like growth factor 2 (“IGF-II”) with high affinity (Frasca et al., 1999; Denley et al., 2004).

The sequence of IR is highly homologous to the sequence of IGF-1R, indicating that their three-dimensional structures are highly likely to be similar. The mature human IR and IGF-1R molecules are each homodimers comprising two α-chains and two β-chains, the α- and β-chains arising from the post-translational cleavage at the furin cleavage site at residues 720-723 (IR-A numbering with the mature N-terminal residue numbered 1) or 707-710 (IGF-1R).

IR is a heavily-glycosylated, disulphide-linked (αβ)₂ homodimer of ˜380 kDa molecular weight. Each IR or IGF-1R monomer comprises, from its N-terminus, a leucine-rich repeat domain (“L1”), a cysteine-rich region (“CR”), a leucine-rich repeat domain (“L2”), three fibronectin Type III domains (“FnIII-1”; “FnIII-2”; and “FnIII-3”), trans- and juxtamembrane segments (“TM” and “JM”), a tyrosine kinase domain (“TK”) and a C-terminal tail (McKern et al., 2006). The FnIII-2 domain contains, within its CC′ loop, an insert domain (“ID”) of ˜120 mostly-disordered residues within which lies the α/β cleavage site. Near the C-terminal region of the IR α-chain lies an amphipathic helical segment (“αCT”) that in apo-IR spans residues 693-710 and packs against the central β-sheet (L1-β₂) of the L1 domain of the alternate IR monomer (Smith et al., 2010). The domain organisation of IR and the structure of apo-IR are presented in FIGS. 1B and 1C.

Intracellularly, the TK domain is flanked by two regulatory regions that contain the phosphotyrosine binding sites for signalling molecules. Each α-chain is linked to its β-chain via a disulphide bond between residues Cys647 and Cys860 (Sparrow et al., 1997) in the case of IR and/or Cys633-Cys849 in the case of IGF-1R. The α-chains of both IR and IGF-1R are cross-linked by disulphide bonds in two places. The first is at Cys524 (IR) or Cys514 (IGF-1R) in the FnIII-1 domain, cross-linked to its counterpart in the opposite monomer, and the second involves one or more of the residues Cys682, Cys683 and Cys685 (1R) or Cys669, Cys670 and Cys672 (IGF-1R) in the insert region of each FnIII-2 domain, cross-linked to their counterparts in the opposite monomer (Sparrow et al., 1997).

The domains of IR and IGF-1R exhibit high (47-67%) amino acid sequence identity indicative of high conservation of three-dimensional structure. The crystal structure of the first three domains of IGF-1R (L1-CR-L2) has been determined (Garrett et al., 1998) and revealed that the L domains consist of a single-stranded right-handed β-helix (a helical arrangement of β-strands), while the cysteine-rich region is composed of eight related disulphide-bonded modules. The crystal structure of the first three domains of IR (L1-CR-L2) has also been determined (WO 07/147,213, Lou et al., 2006) and as anticipated is closely similar to that of its IGF-1R counterpart. Other evidence for the close structural similarity of IR and IGF-1R arises from: (i) electron microscopic analyses (Tulloch et al., 1999), (ii) the fact that hybrid receptors (heterodimers of one IR monomer disulphide-bonded to one of IGF-1R monomer) exist naturally and are commonly found in tissues expressing both receptors (Bailyes et al., 1997), and (iii) the fact that receptor chimeras can be constructed which have whole domains or smaller segments of polypeptide from one receptor replaced by the corresponding domain or sequence from the other (reviewed in Adams et al., 2000). Further to (ii) and (iii) above, physiologically relevant IR/IGF-1R receptor chimeras have been shown to form on cell surfaces (Belfiore et al., 2009).

The current model for insulin binding proposes that, in the basal state, the IR homodimer contains two identical pairs of binding sites (referred to as “Site 1” and “Site 2”) on each monomer (De Meyts and Whittaker, 2002; Schäffer, 1994; De Meyts, 1994; De Meyts, 2004; Kiselyov et al., 2009). Binding of insulin to a low affinity site (“Site 1”) on one α-subunit is followed by a second binding event between the bound insulin and a different region of the second IR α-subunit (“Site 2”). This ligand-mediated bridging between the two α-subunits generates the high affinity state that results in signal transduction. In contrast, soluble IR ectodomain, which is not tethered at its C-terminus, cannot generate the high affinity receptor-ligand complex. The soluble IR ectodomain can bind two molecules of insulin simultaneously at its two Site 1s, but only with nanomolar affinity (Adams et al., 2000).

The model for IGF-I or IGF-II binding to IGF-1R is the same as that just described for insulin binding to IR and involves IGF-I (or IGF-II) binding to an initial low affinity site (“Site 1”) and subsequent cross-linking to a second site (“Site 2”) on the opposite monomer to form the high affinity state, as described for the IR. However, the values of the kinetic parameters describing these events are somewhat different in the two systems (Surinya et al., 2008; Kiselyov et al., 2009).

In addition to the above models of ligand binding, IGF (IGF-I and IGF-II) and insulin have been shown to bind to IR and the IGF-1R, respectively, albeit at a lower affinity than their cognate receptors (Kristensen et al., 1999; Nakae et al., 2001; Kjeldsen et al., 1991). However, as previously mentioned, the IR-A isoform variant of the IR is a high-affinity receptor for IGF-II (Frasca et al., 1999).

While similar in structure, IGF-1R and IR serve different physiological functions. IGF-1R is expressed in almost all normal adult tissue except for liver, which is itself the major site of IGF-I production (Buttel et al., 1999). A variety of signalling pathways are activated following binding of IGF-I or IGF-II to IGF-1R, including Src and Ras, as well as downstream pathways, such as the MAP kinase cascade and the P13K/AKT axis (Chow et al., 1998). IR is primarily involved in metabolic functions whereas IGF-1R mediates growth and differentiation. Consistent with this, ablation of IGF-I (i.e., in IGF-I knock-out mice) results in embryonic growth deficiency, impaired postnatal growth, and infertility. In addition, IGF-1R knock-out mice were only 45% of normal size and died of respiratory failure at birth (Liu et al., 1993). However, both insulin and IGF-I can induce both mitogenic and metabolic effects.

The insulin monomer comprises a 30-residue B-chain and 21-residue A-chain, together containing three α-helices, A1-A8, A12-A18 and B9-B19, connected by three disulphide bonds (Adams et al., 1969). In its pancreatic (storage) form insulin forms a hexamer (a trimer of dimers). The structure of the insulin monomer is presented in FIG. 1A.

Two distinct surfaces of insulin are understood to interact with IR to initiate signalling (Schäffer, 1994). The first (“classical”) surface consists predominantly of residues involved in hormone dimerization, and the second mostly of residues involved in hexamerization (De Meyts, 2004).

The tandem L1-β₂/αCT element from the IR is understood to interact with the classical binding surface of insulin and forms part of Site 1 (Ward and Lawrence, 2009). The second binding surface of insulin is understood to interact with residues at the junction of the FnIII-1 and FnIII-2 domains of the opposite α-chain to that contributing the L1 domain to Site 1 (McKern et al., 2006; Whittaker et al., 2008), referred to as Site 2 (Ward and Lawrence, 2009). IR site 1 is the primary binding hormone site; its dissociation constant for insulin is estimated to be ˜6.4 nM vs ˜400 nM for Site 2 (Kiselyov et al., 2009).

Insulin and the IR ectodomain are proposed to undergo a conformational change upon hormone binding. A key proposed change in insulin is the detachment of the C-terminal B-chain residues B20-B30 (Hua et al., 1991) from the helical core. In the absence of structural characterization of the hormone-receptor complex, however, details of this conformational change have remained speculative. The proposed change in insulin is presented in FIG. 1D.

Insulin remains the key therapeutic for the treatment of both Type 1 and Type 2 diabetes. Its use as a therapeutic has, however, two major complications. The first concerns the method of delivery and the second concerns its profile of action.

In terms of the method of delivery, insulin is not orally bioavailable, and its delivery has to thus be via other means (injection, pumps, pens, nasal sprays, etc.). Formulation of insulin appropriate to each of these means of delivery remains an area of active research.

In terms of profile of action, none of the current modes of delivery can currently deliver insulin in such a way that the respective prandial, post-prandial and sleep concentrations of insulin can be accurately mimicked through a 24-hour cycle.

The above concerns have led to a new class of therapeutics, namely insulin analogues (or “designer” insulins). Examples of designer insulins include:

-   -   1. Humalog™ (or lispro insulin), wherein a two-residue segment         of insulin ProB28-LysB29 is replaced by LysB28-ProB29. This         modification does not alter receptor binding, but blocks the         formation of insulin dimers and hexamers, allowing larger         amounts of active monomeric insulin to be immediately available         upon postprandial injection;     -   2. Lantus™ (or glargine), designed to be a long-acting insulin         analogue. Glargine has a substitution AsnA21Gly and two arginine         residues added to the B-chain C-terminus. Glargine is more         soluble at acidic pH, thus allowing injection of a clear         solution. However, in the neutral subcutaneous space,         higher-order aggregates form, resulting in a slow, peakless         dissolution and absorption of insulin from the site of         injection. It can achieve a peakless level for at least 24         hours; and     -   3. Novolog™ (or aspart insulin), which is another fast-acting         insulin with a substitution ProB28Asp. This analogue has         increased charge repulsion, which prevents the formation of         hexamers, to create faster-acting insulin.

However, the above designer insulins have been developed without the benefit of knowledge of the three-dimensional atomic details of the insulin/IR interaction. The absence of structural data on the insulin/IR complex has hindered a detailed understanding of ligand/IR interactions.

As mentioned above, structural information to date has been available only for insulin and parts of the IR ectodomain. Thus, there has been no structural information detailing the interactions between insulin and the IR, particularly the conformational changes posited to occur on insulin binding to the IR.

Accordingly, there is a need to determine the structure of insulin in complex with IR in order to better understand the nature of the insulin/IR interaction and its role in IR signalling in order to rationally design or redesign agonists and antagonists, particularly alternative insulin analogues, useful inter alia in the treatment of aberrant IR signalling diseases and/or disorders.

SUMMARY OF INVENTION

The present invention is predicated in part by the determination of the crystal structure of insulin in complex with the N- and C-terminal regions of the IR α-chain, which allows visualisation, for the first time, of the long posited conformational change in insulin upon IR binding. The structure also reveals, for the first time, insulin bound in a stabilised form on the L1-β₂ surface of the IR by the αCT recognition helix and shows the accompanied remodelling of the Site 1 L1-β₂/αCT tandem element of the IR upon insulin binding (Smith et al., 2010). The atomic coordinates for the structure are presented in Appendix I.

The crystal structure reveals much needed structural information about insulin residues PheB24 and PheB25 during receptor binding. The critical importance of these insulin residues B24 and B25 for receptor binding is well known (Mayer et al., 2007). Clinical mutations at these sites include PheB24Ser (insulin Los Angeles) and PheB25Leu (insulin Chicago), these having 16% and 1-5% of the activity of normal insulin respectively (Shoelson et al., 1983). Studies have shown that PheB24Gly leads to reduced receptor affinity, while D-Ala and D-Phe substitutions at 1324 results in a 150% and 140-180% increase in affinity relative to native insulin. Modifications to the phenyl ring of B24 mostly results in deleterious effects, while B25 accommodates sizable changes in side-chain structure, but is highly demanding in that the phenyl ring must be positioned at the β-carbon (Quan et al., 2006). A TyrB25 analogue demonstrates full in vitro activity. The significance of the size and orientation of the aromatic side-chain is revealed in the binding affinity for the 1- and 2-naphthylalanine analogues (24% and 50%, respectively). In Contrast, non-aromatic substitution at B25 invariably produces low potency. SerB25 and AlaB25 analogues exhibit respective binding potencies of ˜1% and 7% of native insulin. Distance of the phenyl ring from the backbone appears critical to activity, as the homo-phenylalanine and phenylglycine derivatives are as impotent as the nonaromatic analogues.

Thus, derivatization at insulin residues B24 and B25 appears to modulate the potency of insulin. Accordingly, the present inventors consider that the determination of the crystal structure of human insulin in complex with Site 1 of the human IR α-chain, including detailed structural information regarding the interaction between insulin residues B24 and B25 and IR, will assist in the rational design of insulin B24 and B25 analogues. Similarly, it is considered that the structural information provided concerning the nature of the interactions between insulin B24 and B25 residues and IR, will assist in the use of molecular modelling and related techniques to design insulin analogues that have altered binding affinity and or pharmacological profiles due to their alterations at insulin B24 and/or insulin B25.

With the foregoing in view, one aspect of the present invention provides an insulin/IR α-chain crystalline complex comprising the N- and C-terminal regions of the IR α-chain having the atomic coordinates as set forth in Appendix I. Generally, the crystalline complex comprising insulin and the N- and C-terminal regions of the IR α-chain or their derivatives or components thereof are in essentially pure native form. Derivatives and homologues, higher order complexes and soluble forms of the crystalline complex or its components are also contemplated by the present invention.

Another aspect of the present invention is directed to a data set of atomic coordinates defining the Site 1 interaction between IR including the N- and C-terminal regions of the IR α-chain and insulin.

Yet another aspect of the present invention is directed to conformational mimetics of the Site 1 binding surface of insulin useful as antagonists or agonists of insulin signalling via the IR. The mimetics may interfere or interact directly with Site 1 or may interact elsewhere causing conformational changes to Site 1 or may influence the form or level of the insulin/IR complex.

In particular, a Site 1 antagonist is proposed to, for example, reduce aberrant IR signalling, which as previously mentioned has become implicated in cancer, to reduce the increased glucose uptake attributable to the increased number of IRs on cancer cells.

In particular, a Site 1 antagonist is proposed, for example, in the treatment of cancer by reducing aberrant IR signalling attributable to increased glucose uptake in cancer cells due to an increased number of IRs located on cancer cells.

Likewise, a Site 1 agonist is proposed, for example, in the treatment of both Type 1 and Type 2 diabetes.

More particularly, a Site 1 mimetic molecule is proposed that binds to the low affinity insulin binding site of IR with a high degree of specificity and imparts a selective agonistic or antagonistic activity.

With the foregoing in view, one aspect of the present invention provides an insulin/IR α-chain crystalline complex comprising the N- and C-terminal regions of the IR α-chain having the atomic coordinates as set forth in Appendix I. Generally, the crystalline complex comprising insulin and the N- and C-terminal regions of the IR α-chain or their derivatives or components thereof are in essentially pure native form.

Accordingly, the present invention in one form resides in an insulin/IR complex in crystalline form or a derivative or homologue, higher order complex or soluble form thereof.

In one embodiment the complex comprises the N- and C-terminal regions of the IR α-chain in complex with insulin.

In a preferred embodiment, the complex comprises a leucine-rich repeat domain (“L1”) and an adjacent cysteine-rich region (“CR”) from the N-terminus of the IR α-chain and a portion of an amphipathic helical segment (“αCT”) from the C-terminus of the IR α-chain in complex with insulin.

In a more preferred embodiment, the complex comprises portions of the central fi-shed of the L1 domain and the αCT of the IR α-chain in complex with a portion of insulin.

In a most preferred embodiment, the complex comprises the components of the structure defined by the atomic coordinates shown in Appendix I or a subset thereof.

The present invention in another form provides a method of identifying, designing or screening for a compound that can potentially interact with IR, including performing structure-based identification, design, or screening of a compound based on the compound's interactions with an IR structure defined by the atomic coordinates of Appendix I or a subset thereof.

In another form, the present invention provides a method of identifying, designing or screening for a compound that can potentially mimic insulin interacting with IR, including performing structure-based identification, design, or screening of a compound based on (i) the compound's interaction with an IR structure and/or (ii) the compound's similarity with an insulin structure in complex with an IR structure defined by the atomic coordinates of Appendix 1 or a subset thereof.

In one embodiment, the method includes identifying, designing or screening for a compound which interacts with the three-dimensional structure of the low affinity insulin binding site of IR, the structure being defined by the atomic coordinates shown in Appendix 1, wherein interaction of the compound with the structure is favoured energetically.

In another embodiment, the method includes identifying, designing or screening for a compound based upon the three-dimensional structure of insulin in complex with components of the low affinity insulin binding site of IR, the structure being defined by the atomic coordinates shown in Appendix 1, wherein interaction of the compound with the structure is favoured energetically.

In another embodiment, the method further includes synthesising or obtaining an identified or designed candidate compound and determining the ability of the candidate compound to interact with IR and/or mimic insulin in complex with IR.

The present invention in another form provides a method for identifying an agonist or an antagonist compound comprising an entity selected from the group consisting of an antibody, a peptide, a non-peptide molecule and a chemical compound, wherein said compound is capable of enhancing, eliciting or blocking biological activity resulting from an interaction with insulin and/or the IR, wherein said process includes:

introducing into a suitable computer program parameters defining an interacting surface based on the conformation of insulin and/or IR corresponding to the atomic coordinates of Appendix I or a subset thereof, wherein said program displays a three-dimensional model of the interacting surface;

creating a three-dimensional structure of a test compound in said computer program;

displaying a superimposing model of said test compound on the three-dimensional model of the interacting surface;

assessing whether said test compound model fits spatially and optionally energetically into a binding site;

optionally incorporating said test compound in a biological activity assay; and

optionally determining whether said test compound inhibits or enhances the biological activity of insulin or IR signalling or signalling by a derivative of insulin or IR.

In one embodiment, the method includes identifying an agonist or an antagonist compound capable of interacting with the nanomolar affinity insulin binding site (“Site 1”) of the IR as defined by the atomic coordinates shown in Appendix I.

In a further embodiment, the atomic coordinates as shown in Appendix I or a subset thereof define one or more regions of insulin in complex with N- and C-terminal regions of the IR α-chain.

In a preferred embodiment, the atomic coordinates as shown in Appendix I or a subset thereof define insulin in complex with a L1 domain and an adjacent CR domain from the N-terminus of the IR α-chain and a portion of the αCT from the C-terminus of the IR α-chain.

In another preferred embodiment, the atomic coordinates as shown in Appendix I or a subset thereof define portions of the molecular surface of the central n-sheet of the L1 domain and the αCT of the IR α-chain, which interact with a portion of the molecular surface of insulin.

In a particularly preferred embodiment, the atomic coordinates as shown in Appendix I or a subset thereof define the molecular surface of a B-helix of insulin interacting with the molecular surface of the C-terminal edge of L₁-β₂ of the IR α-chain, the atomic coordinates or a subset thereof defining the B-helix of insulin as lying parallel with and adjacent to a helical portion of the αCT of the IR α-chain.

In another particularly preferred embodiment, the atomic coordinates as shown in Appendix I or a subset thereof define the αCT of the IR α-chain occupying a volume that would otherwise be occupied by the insulin B-chain if insulin was not bound to components of Site 1 of IR. In a more particularly preferred embodiment, a volume that would otherwise be occupied by the C-terminal portion of the B-chain of unbound insulin. In a most particularly preferred embodiment, a volume that would otherwise be occupied by amino acids 26 to 30 from the B-chain of unbound insulin.

In another embodiment, the atomic coordinates define one or more amino acids selected from 1 to 310 and 704 to 719 of the IR α-chain, 1 to 30 from the insulin B-chain and 1 to 21 from the insulin A-chain.

In another preferred embodiment, the one or more amino acids selected from 1 to 310 and 704 to 719 of the IR α-chain include one or more amino acids selected from the group consisting of Asp12, Arg14, Leu36, Leu37, Phe39, Lys40, Leu62, Phe64, Arg65, Phe88, Phe89, Tyr91, Val94, Phe96, Arg118, Glu120, His144, Phe705, Tyr708, Leu709, His710, Asn711, Val712, Val713, Phe714 and Val715.

In another preferred embodiment, the one or more amino acids selected from 1 to 30 from the insulin B-chain include one or more amino acids selected from the group consisting of Gly8, Ser9, Leu11, Val12, Leu15, Tyr16, Phe24, Phe25 and Tyr26.

In another preferred embodiment, the one or more amino acids selected from 1 to 21 from the insulin A-chain include one or more amino acids selected from the group consisting of Gly1, Ile2, Val3, Glu4 and Tyr19.

In another embodiment, IGF-I or IGF-II may be chemically modified to modify the binding affinity of IGF-I or IGF-II to bind to IR as a result of structure-based evaluation using the atomic coordinates as defined in Appendix I or a subset thereof.

In another form, the present invention includes use of the atomic coordinates or a subset thereof as shown in Appendix I at least representing:

-   -   (i) insulin; and/or     -   (ii) one or more regions of insulin in complex with the N- and         C-terminal regions of the IR α-chain,

in identifying, designing or screening for a compound that can potentially mimic insulin interacting with IR, including performing structure-based identification, design, or screening of a compound based on (a) the compound's interactions with an IR structure and/or (b) the compound's similarity with an insulin structure in complex with an IR defined by the atomic coordinates or a subset thereof.

In another form, the present invention includes use of the atomic coordinates or a subset thereof as shown in Appendix I at least representing:

-   -   (i) the N-terminal region of the IR α-chain;     -   (ii) the C-terminal region of the IR α-chain; and/or     -   (iii) one or more regions of the N- and C-terminal regions of         the IR α-chain in complex with insulin,

in identifying, designing or screening for a compound that can potentially interact with IR, including performing structure-based identification, design, or screening of a compound based on the compound's interactions with an IR structure defined by the atomic coordinates or a subset thereof.

In another form, the present invention includes a set of atomic coordinates as shown in Appendix I, or a subset of thereof, at least representing:

-   -   (i) the N-terminal region of the IR α-chain;     -   (ii) the C-terminal region of the IR α-chain;     -   (iii) insulin; and/or     -   (iv) one or more regions of insulin in complex with the N- and         C-terminal regions of the IR α-chain.

In another form, the present invention includes an agonist or antagonist of a site comprising one or more amino acids selected from 1 to 310 and 704 to 719 of the IR α-chain including one or more amino acids selected from the group consisting of Asp12, Arg14, Leu36, Leu37, Phe39, Lys40, Leu62, Phe64, Arg65, Phe88, Phe89, Tyr91, Val94, Phe96, Arg118, Glu120, His144, Phe705, Tyr708, Leu709, His710, Asn711, Val712, Val713, Phe714 and Val715.

In another form, the present invention includes an agonist or antagonist that can potentially mimic insulin interacting with IR, said agonist or antagonist comprising one or more amino acids selected from 1 to 30 from the insulin B-chain including one or more amino acids selected from the group consisting of Gly8, Ser9, Leu11, Val12, Leu15, Tyr16, Phe24, Phe25 and Tyr26.

In another form, the present invention includes an agonist or antagonist that can potentially mimic insulin interacting with IR, said agonist or antagonist comprising one or more amino acids selected from the insulin A-chain including one or more amino acids selected from the group consisting of Gly1, Ile2, Val3, Glu4 and Tyr19.

The present invention has enabled the identification of molecular surface interactions between Site 1 on the IR α-chain and the Site 1 binding surface on insulin. Additionally, the present invention has enabled, for the first time, determination of conformational changes in insulin upon binding to the IR α-chain. In particular, the present invention has enabled the determination of key amino acid residues involved in the binding of insulin to the Site 1 binding surface on the IR α-chain. It will be evident to the skilled person that these findings can be transposed onto related receptors such as the IGF-1R, to which IGF-1 or IGF-II are modelled to bind in a similar fashion as insulin to IR.

The present invention is therefore also useful in the identification, screening and/or design of candidate compounds that bind to Site 1 of IGF-1R.

In one embodiment, candidate compounds for interacting with IR and/or IGF-1R may be chemically modified as a result of structure-based evaluation using the atomic coordinates as defined in Appendix I or a subset thereof.

In another embodiment, the chemical modification is designed to either:

-   -   (i) reduce the potential for the candidate compound to bind to         IR whilst maintaining binding to IGF-1R; or     -   (ii) reduce the potential for the candidate compound to bind to         IGF-1R, whilst maintaining binding to IR.

In another embodiment, insulin may be chemically modified to modify the binding affinity of insulin to bind to IGF-1R as a result of structure-based evaluation using the atomic coordinates as defined in Appendix I or a subset thereof.

The present invention is also useful in the identification, screening and/or design of candidate compounds that bind to IR/IGF-1R receptor chimeras. In particular, the present invention is useful in the identification, screening and/or design of candidate compounds that bind to the Site 1 binding site of an IR/IGF-1R receptor chimera. The Site 1 binding site of the IR/IGF-1R receptor chimera may include the L1 domain from one monomer of one receptor type and the αCT peptide from another monomer of the other receptor type.

In one embodiment, candidate compounds for interacting with an IR/IGF-1R receptor or part thereof may be chemically modified as a result of structure-based evaluation using the atomic coordinates as defined in Appendix I or a subset thereof.

In a particular embodiment, candidate compounds for interacting with a Site 1 binding site of an IR/IGF-1R receptor or part thereof may be chemically modified as a result of structure-based evaluation using the atomic coordinates as defined in Appendix I or a subset thereof.

In another embodiment, a ligand selected from the group consisting of insulin, IGF-I and IGF-II may be chemically modified to modify the binding affinity for the ligand to bind to an IR/IGF-1R receptor or part thereof as a result of structure-based evaluation using the atomic coordinates as defined in Appendix I or a subset thereof.

Candidate compounds and compounds identified or designed using a method or process of the present invention may be any suitable compound, including naturally occurring compounds, de novo designed compounds, library generated compounds (chemically or recombinantly generated), mimetics etc., and may include organic compounds, new chemical entities, antibodies, binding proteins other than antibody-based molecules (non-immunoglobulin proteins) including, for example, protein scaffolds such as lipocalins, designed ankyrin repeat proteins (DARPins, Stumpp et al., 2007) and protein A domains (reviewed in Binz et al, 2005), avimers (Silverman et al., 2005), and other new biological entities such as nucleic acid aptamers (reviewed in Ulrich, 2006).

The present invention is also useful for improving the properties of known ligands for the Site 1 binding site of IR and/or IGF-1R. For example, existing IR or IGF-1R ligands may be screened against the 3D structure of the insulin binding site of IR or a region of the insulin binding site of IR as defined by the atomic coordinates of Appendix I or a subset thereof, and an assessment made of the potential to energetically interact with the insulin binding site of IR.

Similarly, existing IR or IGF-1R Site 1 ligands can be screened against the 3D structure of the binding surface of insulin bound to IR as defined by the atomic coordinates of Appendix I or a subset thereof, and an assessment made of the potential to energetically interact with the insulin binding site of IR.

Thus, the present invention also provides a method of redesigning a compound which is known to bind to IR and/or IGF-1R comprising performing structure-based evaluation of the compound based on the compound's interactions with an IR structure defined by the atomic coordinates of Appendix I or a subset thereof and redesigning or chemically modifying the compound as a result of the evaluation.

In another form, the present invention provides a method of redesigning a compound which is known to bind to IR and/or IGF-IR comprising performing structure-based evaluation of the compound's similarity with an insulin structure in complex with an IR defined by the atomic coordinates of Appendix I or, a subset thereof and redesigning or chemically modifying the compound as a result of the evaluation.

In one embodiment, the compound which is known to bind to IR and/or IGF-1R is redesigned or chemically modified to (i) improve affinity for binding to IR, and/or (ii) lower affinity for binding to IGF-1R.

In another embodiment, the compound which is known to bind to IR and/or IGF-1R is redesigned or chemically modified to (i) improve affinity for binding to IGF-1R, and/or (ii) lower affinity for binding to IR.

In a further embodiment the compound is redesigned or modified so as to lower the affinity to IR or IGF-1R by virtue of the structural information provided by the structure of insulin in complex with the IR α-chain, as defined by the atomic coordinates shown in Appendix I, or a subset thereof.

The present invention also provides a computer system for identifying one or more compounds that can potentially interact with IR and/or IGF-1R, the system containing data representing the structure of: (i) the Site 1 binding site of IR, the structure being defined by a subset of the atomic coordinates shown in Appendix I; (ii) the Site 1 binding site on insulin, the structure being defined by a subset of the atomic coordinates shown in Appendix I; and/or (iii) a combination thereof, the structure being defined by the atomic coordinates shown in Appendix I.

In another aspect, the present invention provides a computer-readable medium having recorded data thereon representing a model and/or the atomic coordinates as shown in Appendix I, or a subset of atomic coordinates thereof, the model and/or the atomic coordinates at least representing:

-   -   (i) the N-terminal region of the IR α-chain;     -   (ii) the C-terminal region of the IR α-chain;     -   (iii) insulin; and/or     -   (iv) one or more regions of insulin in complex with the N- and         C-terminal regions of the IR α-chain.

Also provided are a set of atomic coordinates as shown in Appendix I, or a subset of thereof, at least representing:

-   -   (i) the N-terminal region of the IR α-chain;     -   (ii) the C-terminal region of the IR α-chain;     -   (iii) insulin; and/or     -   (iv) one or more regions of insulin in complex with the N- and         C-terminal regions of the IR α-chain.

The three-dimensional structure of the N- and/or C-terminal regions of the IR α-chain and/or insulin and/or the one or more regions of insulin in complex with the N- and C-terminal regions of the IR α-chain may be used to develop models useful for drug design and/or in silico screening of candidate compounds that interact with and/or modulate IR. Other physicochemical characteristics may also be used in developing the model, e.g. bonding, electrostatics, etc.

Generally, the term “in silico” refers to the creation in a computer memory, i.e., on a silicon or other like chip. Stated otherwise “in silico” means “virtual”. When used herein the term “in silico” is intended to refer to screening methods based on the use of computer models rather than in vitro or in vivo experiments.

Accordingly, the present invention also provides a computer-assisted method of identifying a compound that potentially interacts with IR and/or IGF-1R, which method comprises fitting the structure of: (i) the Site 1 binding site of IR, the structure being defined by a subset of the atomic coordinates shown in Appendix I; and/or (ii) portions of the N- and C-terminal regions of the IR α-chain, which are in complex with insulin, the structure being defined by a subset of the atomic coordinates shown in Appendix I, to the structure of a candidate compound.

Also provided by the present invention is a computer-assisted method for identifying a molecule able to interact with IR and/or IGF-1R using a programmed computer comprising a processor, which method comprises the steps of: (a) generating, using computer methods, a set of atomic coordinates of a structure that possesses energetically favourable interactions with the atomic coordinates of (i) the Site 1 binding site of IR, the structure being defined by a subset of the atomic coordinates shown in Appendix I; and/or (ii) portions of the N- and C-terminal regions of the IR α-chain, which are in complex with insulin, the structure being defined by a subset of the atomic coordinates shown in Appendix I, which coordinates are entered into the computer thereby generating a criteria data set; (b) comparing, using the processor, the criteria data set to a computer database of chemical structures; (c) selecting from the database, using computer methods, chemical structures which are complementary or similar to a region of the criteria data set; and optionally, (d) outputting, to an output device, the selected chemical structures which are complementary to or similar to a region of the criteria data set.

The present invention further provides a computer-assisted method for identifying potential mimetics of IR, insulin and/or IGF-1R using a programmed computer comprising a processor, the method comprising the steps of: (a) generating a criteria data set from a set of atomic coordinates of: (i) the Site 1 binding site of IR, the structure being defined by a subset of the atomic coordinates shown in Appendix I; (ii) portions of the N- and C-terminal regions of the IR α-chain, which are in complex with insulin, the structure being defined by a subset of the atomic coordinates shown in Appendix I; (iii) insulin, the structure being defined by a subset of the atomic coordinates shown in Appendix I; and/or (iv) the Site 1 binding site of insulin or portions thereof, the structure being defined by a subset of the atomic coordinates shown in Appendix I, which coordinates are entered into the computer; (b) (i) comparing, using the processor, the criteria data set to a computer database of chemical structures stored in a computer data storage system and selecting from the database, using computer methods, chemical structures having a region that is structurally similar to the criteria data set; or (ii) constructing, using computer methods, a model of a chemical structure having a region that is structurally similar to the criteria data set; and, optionally, (c) outputting to an output device: (i) the selected chemical structures from step (b)(i) having a region similar to the criteria data set; or (ii) the constructed model from step (b)(ii).

The present invention further provides a method for evaluating the ability of a compound to interact with IR and/or IGF-1R, the method comprising the steps of: (a) employing computational means to perform: (i) a fitting operation between the compound and the binding surface of a computer model of the Site 1 binding site for insulin on IR; and/or (ii) a superimposing operation between the compound and insulin, the Site 1 binding site of insulin, or a portion thereof, using atomic coordinates wherein the root mean square deviation between the atomic coordinates and a subset of atomic coordinates of Appendix I or a subset of atomic coordinates of one or more thereof at least representing the N-terminal region of the IR α-chain, the C-terminal region of IR α-chain, insulin, the Site 1 binding site of insulin, or a portion of the Site 1 binding site of insulin, is not more than 1.5 Å; and (b) analysing the results of the fitting operation and/or superimposing operation to quantify the association between the compound and the binding surface model.

The present invention also provides a method of using molecular replacement to obtain structural information about a molecule or a molecular complex of an unknown structure, comprising the steps of (i) generating an X-ray diffraction pattern of the crystallized molecule or molecular complex; and (ii) applying the atomic coordinates of Appendix I, or a subset of atomic coordinates thereof at least representing the N-terminal region of the IR α-chain, the C-terminal region of IR α-chain, insulin, mimetics thereof, derivatives thereof, or portions thereof, to the X-ray diffraction pattern to generate a three-dimensional electron density map of at least a region of the molecule or molecular complex whose structure, is unknown.

The present invention provides compounds that bind to IR and/or IGF-1R designed, redesigned or modified using the methods or processes of the present invention. Preferably, such compounds have an affinity (K_(d)) for IR and/or IGF-1R of less than 10⁻⁵ M. In a particularly preferred embodiment, the compounds binds to the Site 1 binding site of IR and/or to the Site 1 binding site of IGF-1R.

In view of the high sequence homology between the ligands insulin, IGF-I and IGF-II (Adams et al. 2000), the present invention also encompasses compounds that bind to insulin, IGF-I or IGF-II, said compounds being designed, redesigned or modified using the methods or processes of the present invention.

The present invention also provides a composition comprising a compound of the invention, a peptide or mimetic of the invention, and optionally an acceptable carrier or diluent, more preferably a pharmaceutically acceptable carrier or diluent.

The present invention further provides a method for preventing or treating a disease associated with aberrant IR and/or IGF-1R functioning and/or signalling, the method comprising administering to a subject in need thereof a composition, compound, peptide or mimetic of the invention.

Also provided by the present invention is use of a composition, a compound, a peptide or mimetic of the invention in the manufacture of a medicament for treating a disease or disorder in a subject associated with aberrant IR and/or IGF-1R functioning and/or signalling.

Examples of diseases associated with aberrant IR and/or IGF-1R functioning and/or signalling include, but are not limited to, obesity, type I and type II diabetes, cardiovascular disease, osteoporosis, dementia and cancer.

It is also intended that embodiments of the present invention include manufacturing steps such as incorporating the compound, such as a peptide, into a pharmaceutical composition in the manufacture of a medicament.

Throughout this specification, preferred aspects and embodiments apply, as appropriate, separately, or in combination, to other aspects and embodiments, mutatis mutandis, whether or not explicitly stated as such.

The present invention will now be described further with reference to the following examples, which are illustrative only and non-limiting.

BRIEF DESCRIPTION OF THE DRAWINGS

Various embodiments of the invention will be described with reference to the following drawings. Some of the figures contain colour representations or entities. Coloured versions of the figures are available from the applicant upon request or from an appropriate patent office.

FIG. 1: Shows: (A) a model structure of the insulin monomer in which the A-chain is shown in brown, the B-chain is shown in grey and the three disulphide bonds joining the A-chain to the B-chain are shown in green; (B) a graphical representation of the domain profile of the IR, which, from the N-terminus to the C-terminus shows: a leucine-rich repeat domain (“L1”) shown in cyan; a cysteine-rich region (“CR”) shown in brown; another leucine-rich repeat domain (“L2”) shown in red; three fibronectin Type III domains (“FnIII-1; FnIII-2; and FnIII-3”) shown in green, gold and blue, respectively; trans- and juxtamembrane segments (“TM” and “JM”) shown in grey; a tyrosine kinase domain (“TK”) shown in black and a C-terminal tail shown in grey. The FnIII-2 domain contains an insert domain (“ID”) shown in grey, which contains the α-chain/β-chain cleavage site. An amphipathic helical segment (“αCT”) is positioned at the C-terminal region of the IR α-chain, shown as a magenta circle. Disulphide bonds are shown as green braces above and below the domain profile; (C) a model structure of the IR dimer showing how the IR dimer would sit on the membrane surface. Each monomer of the dimer includes the ectodomain of IR with one monomer shown in ribbon form and the other shown as a space-filled model. The domains of the monomers are coloured as in (B); and (D) a model structure of the insulin monomer modelling the proposed conformational changes to the C-terminal B-chain residues 20 to 30 upon binding to the IR (Hua et al., 1991).

FIG. 2: Shows the crystal structure of insulin in complex with the N- and C-terminal regions of the IR α-chain. The structure is shown in ribbon form with the N-terminal region of the IR α-chain shown with a grey backbone, cyan coloured β-sheets in the L1 domain and gold coloured β-sheets in the CR region. The C-terminal region of the IR α-chain, including the αCT segment, is shown as a magenta coloured α-helix. The insulin monomer is shown with a grey backbone. The α-helices of the A-chain of the insulin monomer are coloured gold and the α-helix of the B-chain is coloured black. The N- and C-termini of the A- and B-chain of the insulin monomer are coloured blue and red, respectively.

FIG. 3: Shows: (A) a model of the crystal structure of insulin in complex with the N- and C-terminal regions of the IR α-chain. The model shows the interaction between insulin and the L1 domain from the N-terminal region of the IR α-chain and the αCT segment from the C-terminal region of the IR α-chain. Secondary structural elements from the L1 domain are coloured cyan with loops shown in white. The A-chain from insulin monomer is coloured brown and the B-chain is coloured black. The αCT segment from the crystal structure is coloured magenta. An αCT segment from a crystal structure of the apo form of the IR, shown in yellow, has been superimposed over the model structure. The N- and C-termini of the A- and B-chain of the insulin monomer and the αCT segments are coloured blue and red, respectively; (B) Insulin B-chain residues Phe24 (F24) and Phe25 (F25) are shown in the model structure from (A), without the apo αCT segment; (C) a model of the crystal structure of insulin in complex with the N- and C-terminal regions of the IR α-chain showing the interface between insulin (A-chain shown in brown and B-chain shown in black), the αCT segment (shown in magenta) and the L1 domain (shown in cyan). Selected residues are shown in stick form. The residues from the insulin B-chain are shown with green carbon atoms. Oxygen atoms are coloured red and nitrogen atoms are coloured blue; (D) a model of the crystal structure of insulin in complex with the N- and C-terminal regions of the IR α-chain showing the interface between insulin (A-chain not shown and B-chain shown in black), the αCT segment (shown in magenta) and the L1 domain (shown in cyan). Selected residues from the L1 domain, the αCT segment and the insulin B-chain are shown with carbon atoms coloured cyan, magenta, green. Oxygen atoms are coloured red and nitrogen atoms are coloured blue.

FIG. 4: Shows a model of the L1 domain (coloured in cyan), the insulin B-chain (coloured in black) and the αCT segment (coloured in magenta) from the crystal structure of insulin in complex with the N- and C-terminal regions of the IR α-chain. The L1 domain, the αCT segment and the insulin B-chain are shown with carbon atoms coloured cyan, magenta, green respectively. Oxygen atoms are coloured red and nitrogen atoms are coloured blue.

FIG. 5: Shows: (A) an SDS-PAGE gel showing bands that correspond to purified cIR485 (lane A), IR310.T (lane B) and L2 domain (lane C); (B) an ion exchange chromatography elution profile showing the elution of fractions corresponding to the L2 domain and IR310.T (in red) against a volume buffer gradient (in blue); (C) a size-exclusion chromatography elution profile showing separation of the IR310.T fraction from (B); (D) an SDS-PAGE gel showing bands that correspond to fractions of IR310.T collected from (C); (E) ITC curves for the titration of zinc-free human insulin against IR310.T precomplexed with a 10 fold molar ratio of αCT⁷⁰⁴⁻⁷¹⁹; and (F) ITC curves for the titration of zinc-free insulin against Fab 83-7 bound IR310.T precomplexed with a 10 fold molar ratio of αCT⁷⁰⁴⁻⁷¹⁹.

FIG. 6: Shows: (A) a model of the L1 domain, the αCT segment, insulin chain-A and insulin chain-B from the crystal structure of insulin in complex with the N- and C-terminal regions of the IR α-chain. The electron difference density maps corresponding to the location of the αCT segment (in magenta), insulin chain-A and insulin chain-B (in yellow) are also shown; (B) a model of Asn11 (coloured in cyan) with an attached glycan (coloured in green) from the crystal structure of the uncomplexed IR485 (Lou et al., 2006) fitted to the difference electron density map of the present invention. Oxygen atoms are coloured red and nitrogen atoms are coloured blue; (C) a model of a portion of αCT segment (coloured magenta) fitted to a difference electron density map shown in magenta. Oxygen atoms are coloured red and nitrogen atoms are coloured blue.

KEY TO SEQUENCE LISTING

SEQ ID NO: 1—Amino acid sequence of mature human insulin receptor (isoform A).

SEQ ID NO: 2—Amino acid sequence of mature human insulin receptor (isoform B).

SEQ ID NO: 3—Amino acid sequence of mature Type 1 insulin-like growth factor receptor.

SEQ ID NO: 4—Amino acid sequence of insulin A-chain.

SEQ ID NO: 5—Amino acid sequence of insulin B-chain.

SEQ ID NO: 6—Amino acid sequence of mature insulin-like growth factor I (“IGF-I”).

SEQ ID NO: 7—Amino acid sequence of mature insulin-like growth factor II (“IGF-II”).

SEQ ID NO: 8—Amino acid sequence of IR310.T.

SEQ ID NO: 9—Amino acid sequence of the IR α-chain C-terminal peptide from the IR-A isoform (“αCT”).

SEQ ID NO: 10—Amino acid sequence of the IR α-chain C-terminal peptide from the IR-B isoform.

SEQ ID NO: 11—Amino acid sequence of MAb 83-7 IgG1 heavy chain.

SEQ ID NO: 12—Amino acid sequence of MAb 83-7 kappa light chain.

SEQ ID NO: 13—Amino acid sequence of Fab 83-7 kappa light chain.

SEQ ID NO: 14—Amino acid sequence of Fab 83-7 IgG1 heavy chain.

SEQ ID NO: 15—Amino acid sequence of cIR485.

DETAILED DESCRIPTION

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art (e.g. in molecular biology, biochemistry, structural biology, and/or computational biology). Standard techniques are used for molecular and biochemical methods (see generally, Sambrook et al., 2001, and Ausubel et al., 1999, which are incorporated herein by reference) and chemical methods.

In the present specification and claims, the word ‘comprising’ and its derivatives including ‘comprises’ and ‘comprise’ include each of the stated integers but does not exclude the inclusion of one or more further integers.

Reference throughout this specification to ‘one embodiment’ or ‘an embodiment’ means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment of the present invention. Thus, the appearance of the phrases ‘in one embodiment’ or ‘in an embodiment’ in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more combinations.

As used herein the term “homologue” means a protein having at least 30% amino acid sequence identity with IR, insulin, IGF-1R, and/or portions thereof. Preferably, the percentage identity is 40 or 50%, more preferably 60 or 70% and most preferably 80 or 90%. A 95% or above identity is most particularly preferred such as 95%, 96%, 97%, 98%, 99% or 100%.

As used herein the term “higher order complex” is used to describe a multimer of the ternary complex of insulin in complex with the IR and the αCT peptide. A higher order complex also includes a co-complex of one or more components of the insulin/IR/αCT complex and another molecule. Various higher order complexes may have different signalling properties.

As used herein the term “derivatives” means IR/insulin/αCT peptide polypeptide complexes that display the biological activity of the wild-type IR/insulin/αCT peptide interactions, characterised by the replacement of at least one amino acid from the wild-type sequence or the modification of one or more of the naturally-occurring amino acids.

Crystals and the Crystal Structure of Insulin in Complex with the N- and C-Terminal Regions of the IR α-Chain

The present invention provides a crystal comprising an N-terminal region of the IR α-chain based on cIR485 (a “cleavable” construct consisting of the first 3 N-terminal domains of the IR α-chain; SEQ ID NO: 15) in complex with Fab 83-7 (SEQ ID NOs 13 and 14), a C-terminal region of the IR α-chain based on the IR classical αCT peptide (“αCT⁷⁰⁴⁻⁷¹⁹”; residues 704-719; Genscript; SEQ ID NO: 9) and human insulin (Sigma-Aldrich; SEQ ID NOs 4 and 5; see Examples).

The crystal structure of human insulin complexed IR310.T/83-7/αCT⁷⁰⁴⁻⁷¹⁹ is presented in FIG. 2. Insulin is seen to interact with both the central β-sheet of the L1 domain and with the αCT peptide. The details of these interactions are presented in FIG. 3. The B-helix of insulin lies along the C-terminal edge of L1-β₂, parallel and adjacent to the helical portion of αCT (FIG. 3A). Although, the insulin A-chain has no interactions with the L1 domain, extensive interactions are observed with the αCT peptide. Critically, the helical component (residues 705-714 in all structures) of the αCT peptide occupies volume that would otherwise be occupied by the insulin B-chain C-terminal segment B26-B30 if the hormone remained in its free conformation (FIG. 3B). No electron density was discerned for insulin B1-B6.

In the human insulin-complexed IR310.T structure, weak electron density extended beyond insulin GluB21 in a direction anti-parallel to the first strand of L1-β2, suggestive of partial ordering of a folded-out B-chain C-terminal strand.

The interface between insulin, the αCT segment and the L1-β₂ surface involves well-defined elements of secondary structure, allowing ready discernment in the electron density maps of the overall direction of the constituent residue side chains. The refined model thus allows key residue-specific interactions at the interface to be discerned with confidence, even though a determination of detailed side-chain conformation is precluded. The major interaction between αCT and insulin is seen to be mediated by the side chains of (a) His710, which is directed into a pocket formed by insulin residues ValA3, GlyB8, SerB9 and ValB12, and (b) Phe714, which is directed into the now exposed hydrophobic crevice of insulin lined by residues GlyA1, IleA2, TyrA19, LeuB11, ValB12 and LeuB15 (FIG. 3C). Asn711 of the αCT peptide is positioned to interact with GlyA1, ValA3 and GluA4. The interaction between the L1 domain and the insulin B-chain helix is not extensive with the side chain of ValB12 being positioned between Phe39, Phe64 and Arg65, while the side chain of TyrB16 is positioned to interact with Phe39 and Lys40 (FIG. 3D). The non-polar face of the amphipathic αCT helix (residues Phe705, Tyr708, Leu709, Val712 and Val 713) engages the non-polar surface of L1-β₂ (Leu36, Leu37, Leu62, Phe64, Phe88, Phe89, Val94 and Phe96). The αCT helix appears to be stabilized further by “clamps” formed by Arg118 and Arg14 (FIG. 3D), with the conformation of Arg118 stabilized by interactions with Tyr91, Glu 120, His144 and Phe705 and the conformation of Arg14 stabilized by interactions with Asp12 and the insulin A-chain C-terminus.

Initially, no interpretable density was discerned for insulin residues B20-B26. Final resolution of residues B20-B26 required careful reprocessing of the X-ray data and re-refinement of the model. Ultimately, B20-B24 could be built in a near native-like conformation, with the side chain of residue B24 directed into a hydrophobic pocket formed by the side chains of residues Phe714, Phe39, Leu37 and LeuB15 (FIG. 4). PheB25 and TyrB26 extended in a non-native-like fashion beyond PheB24 with the side chain of residue TyrB25 directed towards the αCT peptide in the vicinity of residue Val715 and the side chain of residue TyrB26 directed towards the L1 domain residues Arg19 and Asp12.

As used herein, the term “crystal” means a structure (such as a three-dimensional (3D) solid aggregate) in which the plane faces intersect at definite angles and in which there is a regular structure (such as an internal structure) of the constituent chemical species. The term “crystal” refers in particular to a solid physical crystal form such as an experimentally prepared crystal.

Crystals according to the invention may be prepared using any IR ectodomain, i.e., the IR polypeptide containing the extracellular domain, including the N- and C-terminal regions, and lacking the transmembrane domain and the intracellular tyrosine kinase domain. Typically, the extracellular domain comprises residues 1 to 917 (mature receptor numbering) of human IR, or the equivalent thereof together with any post-translational modifications of these residues such as N- or O-linked glycosylation.

In a preferred embodiment the IR polypeptide is human IR (SEQ ID NOs: 1 or 2). However, the IR polypeptide may also be obtained from other species, such as other mammalian, vertebrate or invertebrate species.

Crystals may be constructed with wild-type IR polypeptide ectodomain sequences or variants thereof, including allelic variants and naturally occurring mutations as well as genetically engineered variants. Typically, variants have at least 95 or 98% sequence identity with a corresponding wild-type IR ectodomain polypeptide.

Crystals according to the invention may be prepared using any insulin, i.e., insulin polypeptides containing the insulin A-chain and insulin B-chain. Typically, the insulin will be in a monomeric form.

In a preferred embodiment the insulin polypeptides encode human insulin (SEQ ID NOs: 4 and 5).

Crystals may be constructed with wild-type insulin polypeptide sequences or variants thereof, including allelic variants and naturally occurring mutations as well as genetically engineered variants. Typically, variants have at least 95 or 98% sequence identity with a corresponding wild-type insulin polypeptide.

Optionally, the crystal of the IR ectodomain in complex with insulin may comprise one or more compounds which bind to the ectodomain and/or insulin, or otherwise are soaked into the crystal or co-crystallised with the IR ectodomain and/or insulin. Such compounds include ligands or small molecules, which may be candidate pharmaceutical agents intended to modulate the interaction between IR and insulin or IR and biological targets. The crystal of the IR ectodomain in complex with insulin may also be a molecular complex with other receptors of the IGF receptor family such as IGF-1R (SEQ ID NO: 3). The complex may also comprise additional molecules such as the ligands to these receptors, e.g., IGF-I (SEQ ID NO: 6), IGF-II (SEQ ID NO: 7), etc.

The production of IR ectodomain crystals is described below.

In a preferred embodiment, a crystal of the IR ectodomain in complex with insulin of the invention comprises the N- and C-terminal regions of the IR α-chain in complex with insulin having the atomic coordinates set forth in Appendix I. As used herein, the term “atomic coordinates” or “set of coordinates” refers to a set of values which define the position of one or more atoms with reference to a system of axes. It will be understood by those skilled in the art that the atomic coordinates may be varied, without affecting significantly the accuracy of models derived therefrom. Thus, although the invention provides a very precise definition of a preferred atomic structure, it will be understood that minor variations are envisaged and the claims are intended to encompass such variations.

It will be understood that any reference herein to the atomic coordinates or subset of the atomic coordinates shown in Appendix I shall include, unless specified otherwise, atomic coordinates having a root mean square deviation of backbone atoms of not more than 1.5 Å, preferably not more than 1 Å, when superimposed on the corresponding backbone atoms described by the atomic coordinates shown in Appendix I.

The following defines what is intended by the term “root mean square deviation (‘RMSD’)” between two data sets. For each element in the first data set, its deviation from the corresponding item in the second data set is computed. The squared deviation is the square of that deviation, and the mean squared deviation is the mean of all these squared deviations. The root mean square deviation is the square root of the mean squared deviation.

Preferred variants are those in which the RMSD of the x, y and z coordinates for all backbone atoms other than hydrogen is less than 1.5 Å (preferably less than 1 Å, 0.7 Å or less than 0.3 Å) compared with the coordinates given in Appendix I. It will be readily appreciated by those skilled in the art that a 3D rigid body rotation and/or translation of the atomic coordinates does not alter the structure of the molecule concerned.

In a highly preferred embodiment, the crystal has the atomic coordinates as shown in Appendix I.

The present invention also provides a crystal structure of the Site 1 binding site of IR polypeptide comprising the N- and C-terminal regions of the IR α-chain, or regions thereof.

The atomic coordinates obtained experimentally for: amino acids 5 to 310 (the “N-terminal region of the IR α-chain”) and amino acids 705 to 714 (the “C-terminal region of the IR α-chain”) of human IR-A (mature receptor numbering; SEQ ID NO: 1); amino acids 1 to 20 of the human insulin A-chain; and amino acids 7 to 26 of the human insulin B-chain (SEQ ID NOs: 4 and 5) are shown in Appendix I. However, a person skilled in the art will appreciate that a set of atomic coordinates determined by X-ray crystallography is not without standard error. Accordingly, any set of structure coordinates for an IR polypeptide comprising the N- and C-terminal regions of the IR α-chain in complex with human insulin that has a root mean square deviation of protein backbone atoms of less than 0.75 Å when superimposed (using backbone atoms) on the atomic coordinates listed in Appendix I shall be considered identical.

The present invention also comprises the atomic coordinates of the N- and C-terminal regions of the IR α-chain in complex with insulin that substantially conforms to the atomic coordinates listed in Appendix I.

A structure that “substantially conforms” to a given set of atomic coordinates is a structure wherein at least about 50% of such structure has an RMSD of less than about 1.5 Å for the backbone atoms in secondary structure elements in each domain, and more preferably, less than about 1.3 Å for the backbone atoms in secondary structure elements in each domain, and, in increasing preference, less than about 1.0 Å, less than about 0.7 Å, less than about 0.5 Å, and most preferably, less than about 0.3 Å for the backbone atoms in secondary structure elements in each domain.

In a more preferred embodiment, a structure that substantially conforms to a given set of atomic coordinates is a structure wherein at least about 75% of such structure has the recited RMSD value, and more preferably, at least about 90% of such structure has the recited RMSD value, and most preferably, about 100% of such structure has the recited RMSD value.

In an even more preferred embodiment, the above definition of “substantially conforms” can be extended to include atoms of amino acid side chains. As used herein, the phrase “common amino acid side chains” refers to amino acid side chains that are common to both the structure which substantially conforms to a given set of atomic coordinates and the structure that is actually represented by such atomic coordinates.

As used herein, the term “IR ectodomain” refers to the extracellular domain of IR lacking the transmembrane domain and the intracellular tyrosine kinase domain of IR, typically comprising residues 1 to 917 (mature IR-A receptor numbering), of human IR, or the equivalent thereof, together with any post-translational modifications of these residues such as N- or O-linked glycosylation.

As used herein, the term “low affinity binding site” for IR means the regions of IR involved in forming the nanomolar affinity binding site (also known as “Site 1”) of IR for insulin, comprising the N- and C-terminal regions of the IR α-chain including one or both of the L1 domain of IR and the CR domain of IR. Insulin binding to the low affinity binding site of IR induces formation of the high affinity insulin binding site of IR and subsequent signal transduction.

As used herein, the term “classical α-chain C-terminal peptide”, or “αCT”, refers in IR to a region of the C-terminal α-chain of IR previously described in the literature as being important for insulin binding (Kurose et al., 1994; Kristensen et al, 2002), and comprising amino acids 704-719 (mature IR-A receptor numbering) as given in SEQ ID NO: 9.

As used herein, the term “leucine-rich repeat domain 1” or “L1 domain” refers in IR to a leucine-rich domain comprising amino acids 1-156 of mature human IR (SEQ ID NO: 1). The L1 domain of IR comprises a central β-sheet, which comprises amino acids selected from 10-15, 32-37, 60-65, 88-97, 116-121 and 142-147 of mature human IR (SEQ ID NO: 1).

As used herein, the term “leucine-rich repeat domain 2” or “L2” domain refers in IR to a leucine-rich domain comprising amino acids 310-469 of mature human IR (SEQ ID NO: 1).

As used herein, the term “loop in the fourth leucine-rich repeat (LRR) rung of the L1 domain”, or variations thereof, refers in IR to a leucine-rich domain comprising amino acids 85-91 of mature human IR (SEQ ID NO: 1).

As used herein, the term “cysteine-rich domain” or “CR” domain refers in IR to a cysteine-rich domain comprising amino acids 157-309 of mature human IR (SEQ ID NO: 1). The CR domain contains many different modules. As used herein, the term “module 6 of the CR domain” refers in IR to amino acids 256-286 of mature human IR (SEQ ID NO: 1).

Manipulation of the Atomic Coordinates

It will be appreciated that a set of atomic coordinates for one or more polypeptides is a relative set of points that define a shape in three dimensions. Thus, it is possible that an entirely different set of coordinates could define a similar or identical shape. Moreover, slight variations in the individual coordinates will have little effect on overall shape.

The variations in coordinates may be generated due to mathematical manipulations of the atomic coordinates. For example, the atomic coordinates set forth in Appendix I could be manipulated by crystallographic permutations of the atomic coordinates, fractionalisation of the atomic coordinates, integer additions or subtractions to sets of the structure coordinates, inversion of the atomic coordinates, or any combination thereof.

Alternatively, modification in the crystal structure due to mutations, additions, substitutions, and/or deletions of amino acids, or other changes in any of the components that make up the crystal could also account for variations in atomic coordinates.

Various computational analyses are used to determine whether a molecular complex or a portion thereof is sufficiently similar to all or parts of the structure of the extracellular domain of IR in complex with insulin described above. Such analyses may be carried out in current software applications, such as the Sequoia program (Bruns et al., 1999).

The Molecular Similarity program permits comparisons between different structures, different conformations of the same structure, and different parts of the same structure.

Comparisons typically involve calculation of the optimum translations and rotations required such that the root mean square deviation of the fit over the specified pairs of equivalent atoms is an absolute minimum. This number is given in Angstroms (“Å”).

Accordingly, atomic coordinates of an IR ectodomain comprising the Site 1 binding site in complex with insulin of the present invention include atomic coordinates related to the atomic coordinates listed in Appendix I by whole body translations and/or rotations. Accordingly, RMSD values listed above assume that at least the backbone atoms of the structures are optimally superimposed which may require translation and/or rotation to achieve the required optimal fit from which to calculate the RMSD value.

A three dimensional structure of an IR ectodomain polypeptide or a region thereof and/or a three dimensional structure of an insulin polypeptide or a region thereof which substantially conforms to a specified set of atomic coordinates can be modelled by a suitable modelling computer program such as MODELLER (Sali & Blundell, 1993), using information, for example, derived from the following data: (1) the amino acid sequence of the human IR ectodomain polypeptide and/or the amino acid sequence of the human insulin polypeptide; (2) the amino acid sequence of the related portion(s) of the protein represented by the specified set of atomic coordinates having a three dimensional configuration; and (3) the atomic coordinates of the specified three dimensional configuration. A three dimensional structure of an IR ectodomain polypeptide and/or a three dimensional structure of an insulin polypeptide which substantially conforms to a specified set of atomic coordinates can also be calculated by a method such as molecular replacement, which is described in detail below.

Atomic coordinates are typically loaded onto a machine-readable medium for subsequent computational manipulation. Thus models and/or atomic coordinates are advantageously stored on machine-readable media, such as magnetic or optical media and random-access or read-only memory, including tapes, diskettes, hard disks, CD-ROMs and DVDs, flash memory cards or chips, servers and the interne. The machine is typically a computer.

The atomic coordinates may be used in a computer to generate a representation, e.g. an image of the three-dimensional structure of the IR ectodomain in complex with insulin which can be displayed by the computer and/or represented in an electronic file.

The atomic coordinates and models derived therefrom may also be used for a variety of purposes such as drug discovery, biological reagent (binding protein) selection and X-ray crystallographic analysis of other protein crystals.

Molecular Replacement

The structure coordinates of IR comprising the N- and C-terminal regions of the α-chain in complex with insulin, such as those set forth in Appendix I, or a subset thereof, can also be used for determining the three-dimensional structure of a molecular complex which contains at least the N- and/or C-terminal regions of the α-chain of IR. In particular, structural information about another crystallised molecular complex may be obtained. This may be achieved by any of a number of well-known techniques, including molecular replacement.

Methods of molecular replacement are generally known by those of skill in the art (generally described in Brunger, 1997; Navaza & Saludjian, 1997; Tong & Rossmann, 1997; Bentley, 1997; Lattman, 1985; Rossmann, 1972; McCoy, 2007).

Generally, molecular replacement involves the following steps. X-ray diffraction data are collected from the crystal of a crystallised target structure. The X-ray diffraction data are transformed to calculate a Patterson function. The Patterson function of the crystallised target structure is compared with a Patterson function calculated from a known structure (referred to herein as a search structure). The Patterson function of the search structure is rotated on the target structure Patterson function to determine the correct orientation of the search structure in the crystal. A translation function is then calculated to determine the location of the search structure with respect to the crystal axes. Once the search structure has been correctly positioned in the unit cell, initial phases for the experimental data can be calculated. These phases are necessary for calculation of an electron density map from which structural differences can be observed and for refinement of the structure. Preferably, the structural features (e.g., amino acid sequence, conserved di-sulphide bonds, and beta-strands or beta-sheets) of the search molecule are related to the crystallised target structure.

The electron density map can, in turn, be subjected to any well-known model building and structure refinement techniques to provide a final, accurate structure of the unknown (i.e., target) crystallised molecular complex (e.g. see Jones et al., 1991; Brünger et al., 1998).

Obtaining accurate values for the phases, by methods other than molecular replacement, is a time-consuming process that involves iterative cycles of approximations and refinements and greatly hinders the solution of crystal structures. However, when the crystal structure of a protein containing at least a homologous portion has been solved, the phases from the known structure provide a satisfactory starting estimate of the phases for the unknown structure.

By using molecular replacement, all or part of the structure coordinates of IR comprising the N- and C-terminal regions of the IR α-chain in complex with insulin provided herein (and set forth in Appendix I) can be used to determine the structure of a crystallised molecular complex whose structure is unknown more rapidly and more efficiently than attempting to determine such information ab initio. This method is especially useful in determining the structure of IR.

The structure of any portion of any crystallised molecular complex that is sufficiently homologous to any portion of the extracellular domain of IR and/or IGF-1R can be solved by this method.

Such structure coordinates are also particularly useful to solve the structure of crystals of IR co-complexed with a variety of molecules, such as chemical entities. For example, this approach enables the determination of the optimal sites for the interaction between chemical entities, and the interaction of candidate IR and/or IGF-1R agonists or antagonists.

All of the complexes referred to above may be studied using well-known X-ray diffraction techniques and may be refined against 1.5-3.5 Å resolution X-ray data to an R value of about 0.25 or less using computer software, such as X-PLOR (Yale University, distributed by Molecular Simulations, Inc.; see Brünger, 1996). This information may thus be used to optimize known IR agonist/antagonists, such as anti-IR antibodies, and more importantly, to design new or improved IR agonists/antagonists.

Target Sites for Compound Identification, Design or Screening

The three-dimensional structure of the Site 1 binding site of IR in complex with insulin provided by the present invention (Appendix I) can be used to identify potential target binding sites in the Site 1 binding site of IR and/or IGF-1R (i.e., to identify those regions of the Site 1 binding site of IR and/or IGF-1R involved in and important to the binding of insulin, IGF-I and/or IGF-II and subsequent signal transduction) as well as in methods for identifying or designing compounds which interact with the low affinity binding site of IR and/or IGF-1R, e.g., potential modulators of IR and/or IGF-1R.

The three-dimensional structure of IR in complex with insulin provided by the present invention (Appendix I) can be used to identify potential target binding sites in the L1 domain of IR and/or IGF-1R important for binding to insulin and in the C-terminal region of the IR and/or IGF-1R α-chain important for binding to insulin as well as in methods for identifying or designing compounds which interact with the L1 domain of IR and/or IGF-1R and/or with the C-terminal region of the IR and/or IGF-1R α-chain in a manner similar to insulin in complex with the L1 domain and the C-terminal region of the IR α-chain, e.g., potential modulators of IR and/or IGF-1R.

The low affinity binding site of IR is a region of IR ectodomain involved in insulin docking to the receptor. The preferred low affinity target binding site may comprise the C-terminal region of the IR α-chain and one or more regions from the L1 domain of the IR ectodomain. With regards to the L1 domain, the target binding site preferably comprises portions of the molecular surface of the central β-sheet of L1, preferably containing Asp12, Arg14, Leu 36, Leu 37, Leu62, Phe64, Val94, Phe96, Arg118, Glu120 and His144 and portions of the molecular surface of the second leucine-rich repeat (LRR), preferably containing Phe88, Phe89 and Tyr 91. Most preferably, the low affinity binding site contains both portions of the molecular surface of the central β-sheet of L1 and portions of the molecular surface of the second LRR as defined above.

Alternatively, the low affinity target binding site in IR may comprise one or more amino acids from amino acids 704 to 719 (encompassing the C-terminal region of the IR α-chain) plus one or more of the following amino acid sequences: (i) amino acids 1-156 and (ii) amino acids 157-310.

With regards to amino acids 1-156, the target binding site preferably comprises one or more amino acids selected from Asp12, Arg14, Asn15, Gln34, Leu36, Leu37, Leu62, Phe39, Pro43, Phe46, Leu62, Phe64, Leu87, Phe88, Phe89, Asn90, Val94, Phe96, Glu97, Arg118, Gle120 and His144.

With regards to amino acids 157-310, the target binding site preferably comprises one or more amino acids from the amino acid sequence 192-310, more preferably one or more amino acids from the sequence 227-303, yet more preferably one or more amino acids selected from the sequence 259-284.

In a preferred embodiment, van der Waals and/or hydrophobic interactions account for the major portion of the binding energy between a compound and a low affinity insulin binding site of IR.

The three-dimensional structure of the N- and C-terminal regions of the IR α-chain provided by the present invention can also be used to identify or more clearly elucidate potential target binding sites on IGF-1R ectodomain (i.e., to identify those regions, or at least more accurately elucidate those regions of IGF-1R ectodomain involved in and important to the binding of IGF and signal transduction) as well as in methods used for identifying or designing compounds which interact with potential target binding sites of IGF-IR ectodomain, e.g. potential modulators of IGF-1R.

Preferred target binding sites are those governing specificity, i.e., those regions of IGF-1R ectodomain involved in the initial nanomolar affinity binding of IGF (i.e., the initial binding of IGF to IGF-1R).

The low affinity binding site of IGF-IR is a region of IGF-1R ectodomain involved in IGF-I binding to the receptor. Preferred low affinity target binding sites comprise the C-terminal region of IGF-1R α-chain and one or more regions from the L1 domain and/or the CR domain of IGF-1R ectodomain. With regards to the L1 domain, the target binding site preferably comprises the central β-sheet of the L1 domain, and/or that part of the second LRR containing Ser35, and/or the loop in the fourth LRR rung of the L1 domain, or preferably all of these, as defined above. With regards the CR domain, the target binding site preferably comprises module 6 of the CR domain, as defined above.

In a preferred embodiment, van der Waals and/or hydrophobic interactions account for the major portion of the binding energy between a compound and a low affinity binding site of IGF-1R.

Additional preferred binding sites in the case of both IR and IGF-1R, particularly for biological macromolecules such as proteins or aptamers, are those that are devoid of glycosylation or devoid of steric hindrance from glycan covalently attached to the polypeptide at sites in the spatial vicinity.

Design, Selection, Fitting and Assessment of Chemical Entities that Bind IR and/or IGF-1R

Using a variety of known modelling techniques, the crystal structure of the present invention can be used to produce a model for the low affinity binding site of IR and/or IGF-1R.

As used herein, the term “modelling” includes the quantitative and qualitative analysis of molecular structure and/or function based on atomic structural information and interaction models. The term “modelling” includes conventional numeric-based molecular dynamic and energy minimisation models, interactive computer graphic models, modified molecular mechanics models, distance geometry and other structure-based constraint models.

Molecular modelling techniques can be applied to the atomic coordinates of the low affinity binding site of IR in complex with insulin, or at least part of the C-terminal region of the α-chain of IR or insulin, or regions thereof to derive a range of 3D models and to investigate the structure of binding sites, such as the binding sites of monoclonal antibodies, nonimmunoglobulin binding proteins and inhibitory peptides.

These techniques may also be used to screen for or design small and large chemical entities which are capable of binding IR and modulating the ability of IR to interact with extracellular biological targets, such as insulin or members of the IGF receptor family e.g. which modulate the ability of IR to heterodimerise. The screen may employ a solid 3D screening system or a computational screening system.

Such modelling methods are to design or select chemical entities that possess stereochemical complementary to the low affininty binding site of IR and/or IGF-1R, to the regions of the L1 domain of IR and/or IGF-1R with which the C-terminal region of the α-chain of IR and/or IGF-1R interact, or to the regions of the L1 domain of IR and/or IGF-1R with which insulin or IGF interact. By “stereochemical complementarity” we mean that the compound or a portion thereof makes a sufficient number of energetically favourable contacts with the receptor as to have a net reduction of free energy on binding to the receptor.

Modelling method may also be used to design or select chemical entities that possess stereochemical similarity to the low affinity binding site surface of insulin, to the regions of the A-chain and B-chain of insulin that interact with the C-terminal region of the α-chain of IR or to the regions of the A-chain and B-chain of insulin that interact with the L1 domain of IR. By “stereochemical similarity” we mean that the compound or portion thereof makes about the same number of energetically favourable contacts with the receptor as insulin makes as determined by the crystal structure of insulin in complex with the IR α-chain set out by the coordinates shown in Appendix I.

Stereochemical complementarity is characteristic of a molecule that matches intra-site surface residues lining the groove of the receptor site as enumerated by the coordinates set out in Appendix I or a subset thereof. By “match” we mean that the identified portions interact with the surface residues, for example, via hydrogen bonding or by non-covalent Van der Waals and Coulomb interactions (with surface or residue) which promote desolvation of the molecule within the site, in such a way that retention of the molecule at the binding site is favoured energetically.

It is preferred that the stereochemical complementarity is such that the compound has a K_(d) for the receptor site of less than 10⁻⁴M, more preferably less than 10⁻⁵M and more preferably 10⁻⁶M. In a most preferred embodiment, the K_(d) value is less than 10⁻⁸M and more preferably less than 10⁻⁹M.

Chemical entities which are complementary to the shape and electrostatics or chemistry of the receptor site characterised by amino acids positioned at atomic coordinates set out in Appendix I will be able to bind to the receptor, and when the binding is sufficiently strong, substantially prohibit the interaction of the IR and/or IGF-1R ectodomain with biological target molecules such as insulin or IGF.

It will be appreciated that it is not necessary that the complementarity between chemical entities and the receptor site or similarity between the chemical entities and biological receptor target molecules such as insulin or IGF need extend over all residues of the receptor site or target molecule in order to inhibit or mimic binding of a molecule or complex that naturally interacts with IR and/or IGF-1R ectodomain.

A number of methods may be used to identify chemical entities possessing stereochemical complementarity to the low affinitybinding site of IR and/or IGF-1R, to the regions of the L1 domain of IR and/or IGF-1R with which the C-terminal region of the α-chain of IR and/or IGF-1R interact, or to the regions of the L1 domain of IR and/or IGF-1R with which insulin or IGF interact. For instance, the process may begin by visual inspection of the entire low affinity insulin binding site comprising the N- and C-terminal regions of the α-chain of IR, or the equivalent region in IGF-1R, on the computer screen based on the coordinates in Appendix I generated from the machine-readable storage medium. Alternatively, selected fragments or chemical entities may then be positioned in a variety of orientations, or docked, within the low affinity binding site of IR and/or IGF-1R, or within the L1 domain of IR and/or IGF-1R in a manner similar to insulin and/or the C-terminal region of the α-chain of IR, as defined above. Similar methods could be used to identify chemical entities or compounds that may interact with the L1 domain of IR and/or IGF-1R in a manner similar to that of insulin and/or the C-terminal region of the α-chain of IR.

Modelling software that is well known and available in the art may be used (Guida, 1994). These include. Discovery Studio (Accelrys Software Inc., San Diego), SYBYL (Tripos Associates, Inc., St. Louis, Mo., 1992), Maestro (Schrödinger LLC, Portland), MOE (Chemical Computing Group Inc., Montreal, Canada). This modelling step may be followed by energy minimization with standard molecular mechanics force fields such as AMBER (Weiner et al., 1984), OPLS (Jorgensen and Tirado-Rives, 1988) and CHARMM (Brooks et al., 1983). In addition, there are a number of more specialized computer programs to assist in the process of selecting the binding moieties of this invention.

Specialised computer programs may also assist in the process of selecting fragments or chemical entities. These include, inter alia:

-   -   1. GRID (Goodford, 1985). GRID is available from Molecular         Discovery Ltd., Italy;     -   2. AUTODOCK (Goodsell & Olsen, 1990). AUTODOCK is available from         Scripps Research Institute, La Jolla, Calif.;     -   3. DOCK (Kuntz et al., 1982). DOCK is available from University         of California, San Francisco, Calif.;     -   4. GLIDE (Friesner et al., 2004). GLIDE is available from         Schrödinger LLC, Portland; and     -   5. GOLD (Cole et al., 2005). GOLD is available from The         Cambridge Crystallographic Data Centre, Cambridge, UK.

Once suitable chemical entities or fragments have been selected, they can be assembled into a single compound. In one embodiment, assembly may proceed by visual inspection of the relationship of the fragments to each other on the three-dimensional image displayed on a computer screen in relation to the structure coordinates of the low affinity site of IR, or the L1 domain to which insulin and/or the C-terminal region of the α-chain of IR binds. This is followed by manual model building using software such as Discovery Studio, Maestro, MOE or Sybyl. Alternatively, fragments may be joined to additional atoms using standard chemical geometry.

The above-described evaluation process for chemical entities may be performed in a similar fashion for chemical compounds.

Useful programs to aid one of skilled in the art in connecting the individual chemical entities or fragments include:

-   -   1. CAVEAT (Bartlett et al., 1989). CAVEAT is available from the         University of California, Berkeley, Calif.; and     -   2. GANDI (Day and Caflisch, 2008). GANDI is available from the         University of Zurich.

Other molecular modelling techniques may also be employed in accordance with this invention, see, e.g., Cohen et al. (1990) and Navia & Murcko (1992).

There are two preferred approaches to designing a molecule according to the present invention that complement the stereochemistry of the low affinity binding site of IR and/or IGF-1R, or the L1 domain to which insulin and/or the C-terminal region of the α-chain of IR binds. The first approach is to in silky) directly dock molecules from a three-dimensional structural database, to the target binding site, using mostly, but not exclusively, geometric criteria to assess the goodness-of-fit of a particular molecule to the site. In this approach, the number of internal degrees of freedom (and the corresponding local minima in the molecular conformation space) is reduced by considering only the geometric (hard-sphere) interactions of two rigid bodies, where one body (the active site) contains “pockets” or “grooves” that form binding sites for the second body (the complementing molecule).

Flexibility of the receptor, IR or IGF-1R, can be incorporated into the in silico screening by the application of multiple conformations of the receptor (Totrov and Abagyan, 2008). The multiple conformations of the IR receptor can be generated from the coordinates listed in Appendix I computationally by use of molecular dynamics simulation or similar approaches.

This approach is illustrated by Kuntz et al. (1982) and Ewing et al. (2001), the contents of which are hereby incorporated by reference, whose algorithm for ligand design is implemented in a commercial software package, DOCK version 4.0, distributed by the Regents of the University of California and further described in a document, provided by the distributor, which is entitled. “Overview of the DOCK program suite” the contents of which are hereby incorporated by reference. Pursuant to the Kuntz algorithm, the shape of the cavity in which the C-terminal region of the α-chain of IR fits and/or insulin fits is defined as a series of overlapping spheres of different radii. One or more extant databases of crystallographic data, such as the Cambridge Structural Database System (The Cambridge Crystallographic Data Centre, Cambridge, U.K.), the Protein Data Bank, maintained by the Research Collaboratory for Structural Bioinformatics (Rutgers University, N.J., U.S.A.), LeadQuest (Tripos Associates, Inc., St. Louis, Mo.), Available Chemicals Directory (Symyx Technologies Inc.), and the NCI database (National Cancer Institute, U.S.A) is then searched for molecules which approximate the shape thus defined.

Molecules identified on the basis of geometric parameters, can then be modified to satisfy criteria associated with chemical complementarity, such as hydrogen bonding, ionic interactions and van der Waals interactions. Different scoring functions can be employed to rank and select the best molecule from a database. See for example Bohm & Stahl (1999). The software package FlexX, marketed by Tripos Associates, Inc. (St. Louis, Mo.) is another program that can be used in this direct docking approach (see Rarey et al., 1996).

The second preferred approach entails an assessment of the interaction of respective chemical groups (“probes”) with the active site at sample positions within and around the site, resulting in an array of energy values from which three-dimensional contour surfaces at selected energy levels can be generated. The chemical-probe approach to ligand design is described, for example, by Goodford, (1985), the contents of which are hereby incorporated by reference, and is implemented in several commercial software packages, such as GRID (product of Molecular Discovery Ltd., Italy).

Pursuant to this approach, the chemical prerequisites for a site-complementing molecule are identified at the outset, by probing the active site with different chemical probes, e.g., water, a methyl group, an amine nitrogen, a carboxyl oxygen, or a hydroxyl. Favoured sites for interaction between the active site and each probe are thus determined, and from the resulting three-dimensional pattern of such sites a putative complementary molecule can be generated. This may be done either by programs that can search three-dimensional databases to identify molecules incorporating desired pharmacophore patterns or by programs which use the favoured sites and probes as input to perform de novo design. Suitable programs for determining and designing pharmacophores include CATALYST (Accelrys Software, Inc), and CERIUS2, DISCO (Abbott Laboratories, Abbott Park, Ill.; distributed by Tripos Associates Inc.).

The pharmacophore can be used to screen in silico compound libraries/three-dimensional databases, using a program such as CATALYST (Accelrys Software, Inc) and Sybyl/3DB Unity (Tripos Associates, Inc., St. Louis, Mo.).

Databases of chemical structures are available from a number of sources including Cambridge Crystallographic Data Centre (Cambridge, U.K.), Molecular Design, Ltd., (San Leandro, Calif.), Tripos Associates, Inc. (St. Louis, Mo.), Chemical Abstracts Service (Columbus, Ohio), the Available Chemical Directory (Symyx Technologies, Inc.), the Derwent World Drug Index (WDI), BioByteMasterFile, the National Cancer Institute database (NCI), Medchem Database (BioByte Corp.), and the Maybridge catalogue.

De novo design programs include LUDI (Accelrys Software Inc., San Diego, Calif.), Leapfrog (Tripos Associates, Inc.), and LigBuilder (Peking University, China).

Once an entity or compound has been designed or selected by the above methods, the efficiency with which that entity or compound may bind to IR and/or IGF-1R can be tested and optimised by computational evaluation. For example, a compound that has been designed or selected to function as an IR binding compound must also preferably traverse a volume not overlapping that occupied by the binding site when it is bound to the native IR. An effective IR binding compound must preferably demonstrate a relatively small difference in energy between its bound and free states (i.e., a small deformation energy of binding). Thus, the most efficient IR binding compound should preferably be designed with a deformation energy of binding of not greater than about 10 kcal/mole, preferably, not greater than 7 kcal/mole. IR and/or IGF-1R binding compounds may interact with IR and/or IGF-1R in more than one conformation that are similar in overall binding energy. In those cases, the deformation energy of binding is taken to be the difference between the energy of the free compound and the average energy of the conformations observed when the compound binds to the protein.

A compound designed or selected as binding to IR and/or IGF-1R may be further computationally optimised so that in its bound state it would preferably lack repulsive electrostatic interaction with the target protein.

Such non-complementary (e.g., electrostatic) interactions include repulsive charge-charge, dipole-dipole and charge-dipole interactions. Specifically, the sum of all electrostatic interactions between the compound and the protein when the compound is bound to IR and/or IGF-IR, preferably make a neutral or favourable contribution to the enthalpy of binding.

Once an IR-binding compound and/or IGF-1R-binding compound has been optimally selected or designed, as described above, substitutions may then be made in some of its atoms or side groups to improve or modify its binding properties. Generally, initial substitutions are conservative, i.e., the replacement group will have approximately the same size, shape, hydrophobicity and charge as the original group. It should, of course, be understood that components known in the art to alter conformation should be avoided. Such substituted chemical compounds may then be analysed for efficiency of fit to IR and/or IGF-IR by the same computer methods described in detail above.

Specific computer software is available in the art to evaluate compound deformation energy and electrostatic interaction. Examples of programs designed for such uses include: Gaussian 03, (Frisch, Gaussian, Inc., Pittsburgh, Pa.); GAMESS (Gordon et al., Iowa State University); Jaguar (Schrödinger LLC, Portland); AMBER, version 9.0 (Case et al, University of California at San Francisco); CHARMM (Accelrys Software, Inc., San Diego, Calif.); and GROMACS version 4.0 (van der Spoel et al.).

The screening/design methods may be implemented in hardware or software, or a combination of both. However, preferably, the methods are implemented in computer programs executing on programmable computers each comprising a processor, a data storage system (including volatile and non-volatile memory and/or storage elements), at least one input device, and at least one output device. Program code is applied to input data to perform the functions described above and generate output information. The output information is applied to one or more output devices, in known fashion. The computer may be, for example, a personal computer, microcomputer, or workstation of conventional design.

Each program is preferably implemented in a high level procedural or object-oriented programming language to communicate with a computer system. However, the programs can be implemented in assembly or machine language, if desired. In any case, the language may be compiled or interpreted language.

Each such computer program is preferably stored on a storage medium or device (e.g., ROM or magnetic diskette) readable by a general or special purpose programmable computer, for configuring and operating the computer when the storage media or device is read by the computer to perform the procedures described herein. The system may also be considered to be implemented as a computer-readable storage medium, configured with a computer program, where the storage medium so configured causes a computer to operate in a specific and predefined manner to perform the functions described herein.

Compounds

Compounds of the present invention include both those designed or identified using a screening method of the invention and those which are capable of recognising and binding to the low affinity binding site of IR and/or IGF-1R as defined above. Also encompassed by the present invention are compounds that bind to the L1 domain of IR in a manner similar to that of insulin and/or the C-terminal region of the α-chain of IR, i.e., compounds which mimic insulin and/or the C-terminal region of the α-chain of IR.

Compounds capable of recognising and binding to the low affinity binding site of IR and/or IGF-1R may be produced using (i) a screening method based on use of the atomic coordinates corresponding to the 3D structure of the low affinity binding site of IR in complex with insulin; or (ii) a screening method based on the use of the atomic coordinates corresponding to the 3D structure of insulin in complex with IR. Alternatively, compounds may be identified by screening against a specific target molecule which is indicative of the capacity to bind to the low affinity binding site of IR.

Compounds capable of recognising and binding to the L1 domain of IR and/or IGF-1R in a manner similar to that of insulin and/or the C-terminal region of the α-chain of IR to the L1 domain of IR (i.e. compounds which mimic insulin and/or the C-terminal region of the α-chain of IR) may be produced using a screening method based on use of the atomic coordinates corresponding to the 3D structure of the insulin and/or the C-terminal region of the α-chain of IR in isolation or as it associates with IR, or alternatively may be identified by screening against a specific target molecule which is indicative of the capacity to bind to the low affinity binding site of IR.

The candidate compounds and/or compounds identified or designed using a method of the present invention may be any suitable compound, synthetic or naturally occurring, preferably synthetic. In one embodiment, a synthetic compound selected or designed by the methods of the invention preferably has a molecular weight equal to or less than about 5000, 4000, 3000, 2000, 1000 or 500 daltons. A compound of the present invention is preferably soluble under physiological conditions.

The compounds may encompass numerous chemical classes, though typically they are organic molecules, preferably small organic compounds having a molecular weight of more than 50 and less than about 2,500 daltons, preferably less than 1,500, more preferably less than 1,000 and yet more preferably less than 500. Such compounds can comprise functional groups necessary for structural interaction with proteins, particularly hydrogen bonding, and typically include at least an amine, carbonyl, hydroxyl or carboxyl group, preferably at least two of the functional chemical groups. The compound may comprise cyclical carbon or heterocyclic structures and/or aromatic or polyaromatic structures substituted with one or more of the above functional groups. Compounds can also comprise biomolecules including peptides, saccharides, fatty acids, steroids, purines, pyrimidines, derivatives, structural analogues, or combinations thereof.

Compounds may include, for example: (1) peptides such as soluble peptides, including Ig-tailed fusion peptides and members of random peptide libraries (see, e.g., Lam et al., 1991; Houghten et al., 1991) and combinatorial chemistry-derived molecular libraries made of D- and/or L-configuration amino acids; (2) phosphopeptides (e.g., members of random and partially degenerate, directed phosphopeptide libraries, see, e.g., Songyang et al., 1993); (3) antibodies (e.g., polyclonal, monoclonal, humanized, anti-idiotypic, chimeric, and single chain antibodies as well as Fab, (Fab)_(2′), Fab expression library and epitope-binding fragments of antibodies); (4) nonimmunoglobulin binding proteins such as but not restricted to avimers, DARPins and lipocalins; (5) nucleic acid-based aptamers; and (6) small organic and inorganic molecules.

Ligands can be obtained from a wide variety of sources including libraries of synthetic or natural compounds. Synthetic compound libraries are commercially available from, for example, Maybridge Chemical Co. (Tintagel, Cornwall, UK), AMRI (Budapest, Hungary) and ChemDiv (San Diego, Calif.), Specs (Delft, The Netherlands).

Natural compound libraries comprising bacterial, fungal, plant or animal extracts are available from, for example, Pan Laboratories (Bothell, Wash.), TimTec (Newark, Del.). In addition, numerous means are available for random and directed synthesis of a wide variety of organic compounds and biomolecules, including expression of randomized oligonucleotides.

Alternatively, libraries of natural compounds in the form of bacterial, fungal, plant and animal extracts can be readily produced. Methods for the synthesis of molecular libraries are readily available (see, e.g., DeWitt et al., 1993; Erb et al., 1994; Zuckermann et al., 1994; Cho et al., 1993; Carell et al., 1994a; Carell et al., 1994b; and Gallop et al., 1994). In addition, natural or synthetic compound libraries and compounds can be readily modified through conventional chemical, physical and biochemical means (see, e.g., Blondelle and Houghton, 1996), and may be used to produce combinatorial libraries. In another approach, previously identified pharmacological agents can be subjected to directed or random chemical modifications, such as acylation, alkylation, esterification, amidification, and the analogues can be screened for IR and/or IGF-1R-modulating activity.

Numerous methods for producing combinatorial libraries are known in the art, including those involving biological libraries; spatially addressable parallel solid phase or solution phase libraries; synthetic library methods requiring deconvolution; the “one-bead one-compound” library method; and synthetic library methods using affinity chromatography selection. The biological library approach is limited to polypeptide or peptide libraries, while the other four approaches are applicable to polypeptide, peptide, nonpeptide oligomer, or small molecule libraries of compounds (Lam, 1997).

Compounds also include those that may be synthesized from leads generated by fragment-based drug design, wherein the binding of such chemical fragments is assessed by soaking or co-crystallizing such screen fragments into crystals provided by the invention and then subjecting these to an X-ray beam and obtaining diffraction data. Difference Fourier techniques are readily applied by those skilled in the art to determine the location within the IR ectodomain structure at which these fragments bind, and such fragments can then be assembled by synthetic chemistry into larger compounds with increased affinity for the receptor.

Isolated Peptides or Mimetics Thereof.

Compounds identified or designed using the methods of the invention can be a peptide or a mimetic thereof.

The isolated peptides or mimetics of the invention may be conformationally constrained molecules or alternatively molecules which are not conformationally constrained such as, for example, non-constrained peptide sequences. The term “conformationally constrained molecules” means conformationally constrained peptides and conformationally constrained peptide analogues and derivatives.

The term “analogues” refers to molecules having a chemically analogous structure to naturally occurring α-amino acids. Examples include molecules containing gem-diaminoalkyl groups or alklylmalonyl groups.

The term “derivatives” includes α-amino acids wherein one or more side groups found in the naturally occurring α-amino acids have been modified. Thus, for example the amino acids may be replaced with a variety of uncoded or modified amino acids such as the corresponding D-amino acid or N-methyl amino acid. Other modifications include substitution of hydroxyl, thiol, amino and carboxyl functional groups with chemically similar groups.

With regard to peptides and mimetics thereof, other examples of other unnatural amino acids or chemical amino acid analogues/derivatives which can be introduced as a substitution or addition include, but are not, limited to, 2,4-diaminobutyric acid, α-amino isobutyric acid, 4-aminobutyric acid, 2-aminobutyric acid, 6-amino hexanoic acid, 2-amino isobutyric acid, 3-amino propionic acid, ornithine, norleucine, norvaline, hydroxyproline, sarcosine, citrulline, homocitrulline, cysteic acid, t-butylglycine, t-butylalanine, phenylglycine, cyclohexylalanine, β-alanine, fluoro-amino acids, designer amino acids such as β-methyl amino acids, Cα-methyl amino acids, Nα-methyl amino acids, and amino acid analogues in general.

The mimetic may be a peptidomimetic. A “peptidomimetic” is a molecule that mimics the biological activity of a peptide but is no longer peptidic in chemical nature. By strict definition, a peptidomimetic is a molecule that no longer contains any peptide bonds (that is, amide bonds between amino acids). However, the term peptide mimetic is sometimes used to describe molecules that are no longer completely peptidic in nature, such as pseudo-peptides, semi-peptides and peptoids. Whether completely or partially non-peptide, peptidomimetics for use in the methods of the invention, and/or of the invention, provide a spatial arrangement of reactive chemical moieties that closely resembles the three-dimensional arrangement of active groups in the peptide on which the peptidomimetic is based. As a result of this similar active-site geometry, the peptidomimetic has effects on biological systems which are similar to the biological activity of the peptide.

There are sometimes advantages for using a mimetic of a given peptide rather than the peptide itself, because peptides commonly exhibit two undesirable properties: (1) poor bioavailability; and (2) short duration of action. Peptide mimetics offer an obvious route around these two major obstacles, since the molecules concerned are small enough to be both orally active and have a long duration of action. There are also considerable cost savings and improved patient compliance associated with peptide mimetics, since they can be administered orally compared with parenteral administration for peptides. Furthermore, peptide mimetics are generally cheaper to produce than peptides.

Suitable peptidomimetics based on insulin, a fragment thereof, and/or the C-terminal region of the α-chain of IR and/or IGR-1R can be developed using readily available techniques. Thus, for example, peptide bonds can be replaced by non-peptide bonds that allow the peptidomimetic to adopt a similar structure, and therefore biological activity, to the original peptide. Further modifications can also be made by replacing chemical groups of the amino acids with other chemical groups of similar structure. The development of peptidomimetics derived from peptides of insulin, a fragment thereof, and/or the C-terminal region of the IR and/or IGF-1R α-chain can be aided by reference to the three dimensional structure of these residues as provided in Appendix I. This structural information can be used to search three-dimensional databases to identify molecules having a similar structure, using programs such as Sybyl/3DB Unity (Tripos Associates, St. Louis, Mo.).

Those skilled in the art will recognize that the design of a peptidomimetic may require slight structural alteration or adjustment of a chemical structure designed or identified using the methods of the invention. In general, chemical compounds identified or designed using the methods of the invention can be synthesized chemically and then tested for ability to modulate IR and/or IGF-1R activity using any of the methods described herein. The methods of the invention are particularly useful because they can be used to greatly decrease the number potential mimetics which must be screened for their ability to modulate IR and/or IGF-1R activity.

The peptides or peptidomimetics of the present invention can be used in assays for screening for candidate compounds which bind to regions of IR and/or IGF-1R and potentially interfere with the binding of insulin to IR and/or signal transduction and/or the binding of IGF to IGF-1R and/or signal transduction. Peptides or peptidomimetics which mimic target binding sites are particularly useful as specific target molecules for identifying potentially useful ligands for IR and/or IGF-IR.

Standard solid-phase ELISA assay formats are particularly useful for identifying compounds that bind to the receptor. In accordance with this embodiment, the peptide or peptidomimetic immobilized on a solid matrix, such as, for example an array of polymeric pins or a glass support. Conveniently, the immobilized peptide or peptidomimetic is a fusion polypeptide comprising Glutathione-5-transferase (GST; e.g. a CAP-ERK fusion), wherein the GST moiety facilitates immobilization of the protein to the solid phase support. This assay format can then be used to screen for candidate compounds that bind to the immobilised peptide or peptidomimetic and/or interfere with binding of a natural binding partner of IR and/or IGF-IR to the immobilised peptide or peptidomimetic.

As used herein a “fragment” is a portion of a peptide of the invention which maintains a defined activity of the “full-length” peptide, namely the ability to bind to the low affinity binding site of IR and/or IGF-1R, or to bind to the L1 domain of IR and/or IGF-1R. Fragments can be any size as long as they maintain the defined activity. Preferably, the fragment maintains at least 50%, more preferably at least 75%, of the activity of the full length polypeptide.

The % identity of a peptide is determined by GAP (Needleman and Wunsch, 1970) analysis (GCG program) with a gap creation penalty=5, and a gap extension penalty=0.3. The query sequence is at least 10 amino acids in length, and the GAP analysis aligns the two sequences over a region of at least 10 amino acids. More preferably, the GAP analysis aligns two sequences over their entire length.

With regard to a defined peptide, it will be appreciated that % identity figures higher than those provided above will encompass preferred embodiments. Thus, where applicable, in light of the minimum % identity figures, it is preferred that the peptide comprises an amino acid sequence which is at least 50%, more preferably at least 55%, more preferably at least 60%, more preferably at least 65%, more preferably at least 70%, more preferably at least 75%, more preferably at least 80%, more preferably at least 85%, more preferably at least 90%, more preferably at least 91%, more preferably at least 92%, more preferably at least 93%, more preferably at least 94%, more preferably at least 95%, more preferably at least 96%, more preferably at least 97%, more preferably at least 98%, more preferably at least 99%, more preferably at least 99.1%, more preferably at least 99.2%, more preferably at least 99.3%, more preferably at least 99.4%, more preferably at least 99.5%, more preferably at least 99.6%, more preferably at least 99.7%, more preferably at least 99.8%, and even more preferably at least 99.9% identical to the relevant nominated SEQ ID NO.

Amino acid sequence mutants of the peptides identified or designed using the methods of the invention, and/or of the present invention, can be prepared by introducing appropriate nucleotide changes into a nucleic acid of the present invention, or by in vitro synthesis of the desired peptide. Such mutants include, for example, deletions, insertions or substitutions of residues within the amino acid sequence. A combination of deletion, insertion and substitution can be made to arrive at the final construct, provided that the final peptide product possesses the desired characteristics.

In designing amino acid sequence mutants, the location of the mutation site and the nature of the mutation will depend on characteristic(s) to be modified. The sites for mutation can be modified individually or in series, e.g., by (1) substituting first with conservative amino acid choices and then with more radical selections depending upon the results achieved, (2) deleting the target residue, or (3) inserting other residues adjacent to the located site.

Substitution mutants have at least one amino acid residue in the peptide removed and a different residue inserted in its place. Sites of interest are those in which particular residues obtained from various strains or species are identical. These sites, especially those falling within a sequence of at least three other identically conserved sites, are preferably substituted in a relatively conservative manner. Such conservative substitutions are shown in Table 1 under the heading of “exemplary substitutions”.

TABLE 1 Exemplary substitutions. Original Exemplary Residue Substitutions Ala (A) val; leu; ile; gly Arg (R) lys Asn (N) gln; his Asp (D) glu Cys (C) ser Gln (Q) asn; his Glu (E) asp Gly (G) pro, ala His (H) asn; gln Ile (I) leu; val; ala Leu (L) ile; val; met; ala; phe Lys (K) arg Met (M) leu; phe Phe (F) leu; val; ala Pro (P) gly Ser (S) thr Thr (T) ser Trp (W) tyr Tyr (Y) trp; phe Val (V) ile; leu; met; phe, ala

In a preferred embodiment a mutant/variant peptide has one or two or three or four conservative amino acid changes when compared to a peptide defined herein. Details of conservative amino acid changes are provided in Table 1.

Also included within the scope of the invention are peptides which are differentially modified during or after synthesis, e.g., by biotinylation, benzylation, glycosylation, acetylation, phosphorylation, amidation, derivatization by known protecting/blocking groups, proteolytic cleavage, linkage to an antibody molecule or other cellular ligand, etc. These modifications may serve to increase the stability and/or bioactivity of the peptide.

The residues that form the αCT segment of the IR α-chain, namely residues 704 to 719, can be grouped into four classes: Class A—those whose side chains are completely buried in the interface with insulin (His710, Asn711 and Phe714); Class B—those whose sides chains are completely buried in the interface with L1 (Phe703, Phe705 Tyr708, Leu709, Val712, Val713); Class C—those whose side chains lie at the periphery of the interface with insulin and/or the L1 domain; and Class D—those whose side chains appear to have no interaction with insulin or L1. In terms of using the αCT segment itself as a scaffold for mimetics that might compete with the naturally-occurring αCT segment in its binding to insulin and/or the L1 domain, design might focus in the first instance on substitution of those residues belonging to Class C, given that the residues lying in Classes A and B are relatively optimally packed within the interfaces and already have few degrees of freedom. Higher affinity binding might be achieved by substitution of one or more of the Class C residues with either naturally-occurring amino acids or non-natural amino acids. For example, the substitution of one or more of the charged residues with residues that have reduced rotameric degrees of freedom (i.e., reduced entropy) may lead to higher affinity binding or altered physicochemical properties of the compound. Such modification for example may include substitution by the naturally-occurring amino acids Phe, Tyr or Trp. As a further example, it may be possible to substitute residues with more bulky non-natural amino acids that retain the terminal cationic character, for example substitution by the basic phenyl propanoic acid derivatives App (L-2-amino-3-(4-aminophenyl)propanoic acid) and/or Gpp, (L-2-amino-3-(4-guanidinophenyl)propanoic acid) (Svenson et al., 2009). A further strategy for design might involve substitutions to improve the overall stability of the helical structure (for example helix stapling—see Danial et al., 2008). Such substitutions would likely be made within Class D residues. A yet further strategy to improve affinity or physicochemical properties might involve truncation of the helical segment and/or attaching an N- or C-terminal group also designed to improve affinity. Similar principles of design may be applied to generate modified peptides based on the corresponding native IGF-1R peptide as outlined above for the IR peptide.

Likewise, the residues that form the Site 1 binding surface of insulin can be grouped into five classes: Class A—those whose side chains are complete buried in the interface with the L1 domain (TyrB16, PheB24); Class B—those whose sides chains are completely buried in the interface with the αCT segment (ValA3, GlyB8, SerB9, GlyA1, IleA2, TyrA19, LeuB11, LeuB15, GluA4 and PheB25); Class C—those whose side chains mediate the interface with both the L1 domain and the αCT segment (ValB12 and TyrB26); Class D—those whose side chains lie at the periphery of the interface with the L1 domain and/or the αCT segment; and Class E—those whose side chains appear to have no interaction with the L1 domain or the αCT segment. In terms of using the insulin monomer as defined in complex with IR itself as a scaffold for mimetics that might compete with the naturally-occurring insulin in its binding to the L1 domain and/or the αCT segment, design might focus in the first instance on substitution of those residues belonging to Class D, given that the residues lying in Classes A and B are relatively optimally packed within the interfaces and already have few degrees of freedom. Higher affinity binding might be achieved by substitution of one or more of the Class D residues with either naturally-occurring amino acids or non-natural amino acids. For example, the substitution of one or more of the charged residues with residues that have reduced rotameric degrees of freedom (i.e., reduced entropy) may lead to higher affinity binding or altered physicochemical properties of the compound. Such modification for example may include substitution by the naturally-occurring amino acids Phe, Tyr or Trp. As a further example, it may be possible to substitute residues with more bulky non-natural amino acids that retain the terminal cationic character, for example substitution by the basic phenyl propanoic acid derivatives App (L-2-amino-3-(4-aminophenyl)propanoic acid) and/or Gpp, (L-2-amino-3-(4-guanidinophenyl)propanoic acid) (Swenson et, al., 2009). A further strategy for design might involve substitutions to improve the overall stability of the conformational change in insulin upon binding to the IR. Such substitutions would likely be made within Class E residues. A yet further strategy to improve affinity or physicochemical properties might involve truncation of the C-terminus residues B26 to B30 and/or attaching an N- or C-terminal group also designed to improve affinity. Similar principles of design may be applied to generate modified peptides based on the corresponding native IGF-1R peptide as outlined above for the IR peptide.

The design of synthetic non-peptide mimetics of α-helices is an established art (see for example Davis et al., 2006). In particular, methods of mimicry of i, i+4, i+7 motifs (such as those identified within the αCT segment of the α-chain of IR and IGF-1R and which interact the respective L1 domains are known. For example, these motifs may be mimicked by terphenyl, oligophenyl, chalcone or 1,4-benzodiazepine-2,5-dione scaffolds (Davis et al., 2006) or by benzoylurea scaffolds (US 2008153802). Non-peptide mimetics of α-helices have been investigated as therapeutics in a number of disease contexts, for example HIV1 infection (disruption of the assembly of the hexameric helical bundle (Ernst et al., 2001)) and cancer (disruption of the assembly of the HDM2-p53 complex (Yin et al., 2005); inhibitors of Bcl-2 family heterodimerisation (Degterev et al., 2001).

With regard to redesigning compounds using a method of the invention, in an embodiment the compound is redesigned to be more structurally similar to the native αCT segment of the α-chain of IR and/or the αCT segment of the α-chain of IGF-1R. Examples of peptides which could be redesigned in this manner include, but are not limited to, those described by Schäffer et al. (2003) and/or U.S. Pat. No. 7,173,005.

In an alternative embodiment, the compound is redesigned to be more structurally similar to native insulin in complex with the IR. Preferably, the compound is redesigned to mimic the conformational structural changes in insulin upon binding to the IR. More preferably, the compound is redesigned to mimic the conformational structural changes in the insulin B-chain upon binding to the IR.

Interaction of Compounds with IR and/or IGF-1R

A compound may interact with the low affinity binding site of IR and/or IGF-1R by binding either directly or indirectly to that region. A compound which binds directly, binds to the specified region. A compound which binds indirectly, binds to a region in close proximity to or adjacent to the low affinity binding site of IR and/or IGF-1R with the result that it interferes with the ability of IR to bind to insulin, or IGF-1R to bind IGF, either antagonistically or agonistically. Such interference may be steric, electrostatic, or allosteric. Preferably, a compound interacts with the low affinity binding site of IR and/or IGF-1R by binding directly to the specified region. In the case of compounds that bind to specific target molecules, such compounds bind directly to the specific target molecule.

A compound may alternatively interact with the L1 domain of IR and/or IGF-1R in a manner similar to that of the αCT segment of the α-chain of IR by binding either directly or indirectly to that region. A compound which binds directly, binds to the specified region. A compound which binds indirectly, binds to a region in close proximity to or adjacent to the L1 domain of IR and/or IGF-1R in a manner similar to that of the αCT segment of the α-chain of IR with the result that it interferes with the ability of IR to bind to insulin, or IGF-1R to bind IGF, either antagonistically or agonistically. Such interference may be steric, electrostatic, or allosteric. Preferably, a compound interacts with the L1 domain of IR and/or IGF-1R in a manner similar to that of the αCT segment of the α-chain of IR by binding directly to the specified region. In the case of compounds that bind to specific target molecules, such compounds bind directly to the specific target molecule.

Binding can be either by covalent or non-covalent interactions, or both. Examples of non-covalent interactions include electrostatic interactions, van der Waals interactions, hydrophobic interactions and hydrophilic interactions.

When a compound of the invention interacts with IR and/or IGF-1R, it preferably “modulates” IR or IGF-1R, respectively. By “modulate” we mean that the compound changes an activity of IR or IGF-1R by at least 10%. Suitably, a compound modulates IR or IGF-1R by increasing or decreasing signal transduction via IR or IGF-1R, respectively. The phrase “decreases signal transduction” is intended to encompass partial or complete inhibition of signal transduction via IR or IGF-1R. The ability of a candidate compound to increase or decrease signal transduction via IR or IGF-1R can be assessed by any one of the IR or IGF-1R cell-based assays described herein.

Compounds may act as antagonists or agonists for insulin binding to IR or as antagonists or agonists for IGF binding to IGF-1R.

Compounds of the present invention preferably have an affinity for IR or IGF-1R sufficient to provide adequate binding for the intended purpose. Suitably, such compounds and compounds which bind to specific target molecules of IR or IGF-1R have an affinity (K_(d)) of from 10⁻⁵ to 10⁻¹⁵ M. For use as a therapeutic, the compound suitably has an affinity (K_(d)) of from 10⁻⁷ to 10⁻¹⁵ M, preferably from 10⁻⁸ to 10⁻¹² M and more preferably from 10⁻¹⁰ to 10⁻¹² M. Where a compound is to be used as a reagent in a competitive assay to identify other ligands, the compound suitably has an affinity (K_(d)) of from 10⁻⁵ to 10⁻¹² M.

As will be evident to the skilled person, the crystal structure presented herein has enabled, for the first time, direct visualisation of the regions binding insulin in the IR. The structure has enabled the identification of the αCT segment of the α-chain of IR, critical for the initial binding of insulin, and in the subsequent formation of the high affinity insulin-IR complex that leads to signal transduction.

In one preferred embodiment, a compound has a high specificity for IR and/or a specific target molecule of IR but not for IGF-1R, i.e., a compound selectively binds to IR or has enhanced selectivity for IR over IGF-1R. In this respect, a compound suitably has an affinity (IQ) for IR and/or a specific target molecule of IR of no more than 10⁻⁵ M, preferably no more than 10⁻⁷ M, and an affinity for IGF-1R of at least 10⁻⁵ M, preferably at least 10⁻³ M. Such compounds are desirable as, for example, IR agonists where the propensity to interact with IGF-1R and thus, for example, promote undesirable cell proliferation, is reduced.

In a preferred embodiment, the (IR or specific target molecule of IR)/IGF-1R binding affinity ratio for a compound is at least 10 and preferably at least 100.

In another preferred embodiment, a compound has a high specificity for IGF-1R and/or a specific target molecule of IGF-1R but not for IR, i.e., a compound selectively binds to IGF-1R or has enhanced selectivity for IGF-1R over IR. In this respect, a compound suitably has an affinity (IQ) for IGF-1R and/or a specific target molecule of IGF-1R of no more than 10⁻⁵ M, preferably no more than 10⁻⁷ M, and an affinity for IR of at least 10⁻⁵ M, preferably at least 10⁻³ M. Such compounds are desirable as, for example, IGF-1R agonists where there propensity to interact with IR and thus, for example, promote glucose uptake and metabolism, is reduced.

In a preferred embodiment, the (IGF-1R or specific target molecule of IGF-1R)/(IR) binding affinity ratio for a compound is at least 10 and preferably at least 100.

Screening Assays and Confirmation of Binding

Compounds of the invention may be subjected to further confirmation of binding to IR and/or IGF-1R by co-crystallization of the compound with IR and/or IGF-1R and structural determination, as described herein.

Compounds designed or selected according to the methods of the present invention are preferably assessed by a number of in vitro and in vivo assays of IR and/or IGF-1R function to confirm their ability to interact with and modulate IR and/or IGF-1R activity. For example, compounds may be tested for their ability to bind to IR and/or IGF-1R and/or for their ability to modulate e.g. disrupt, IR and/or IGF-1R signal transduction.

Libraries may be screened in solution by methods generally known in the art for determining whether ligands competitively bind at a common binding site. Such methods may include screening libraries in solution (e.g., Houghten, 1992), or on beads (Lam, 1991), chips (Fodor, 1993), bacteria or spores (U.S. Pat. No. 5,223,409), plasmids (Cull et al., 1992), or on phage (Scott & Smith, 1990; Devlin, 1990; Cwirla et al., 1990; Felici, 1991; U.S. Pat. No. 5,223,409).

Where the screening assay is a binding assay, IR or IGF-1R may be joined to a label, where the label can directly or indirectly provide a detectable signal. Various labels include radioisotopes, fluorescent molecules, chemiluminescent molecules, enzymes, specific binding molecules, particles, e.g., magnetic particles, and the like. Specific binding molecules include pairs, such as biotin and streptavidin, digoxin and antidigoxin, etc. For the specific binding members, the complementary member would normally be labelled with a molecule that provides for detection, in accordance with known procedures.

A variety of other reagents may be included in the screening assay. These include reagents like salts, neutral proteins, e.g., albumin, detergents, etc., which are used to facilitate optimal protein-protein binding and/or reduce non-specific or background interactions. Reagents that improve the efficiency of the assay, such as protease inhibitors, nuclease inhibitors, antimicrobial agents, etc., may be used. The components are added in any order that produces the requisite binding. Incubations are performed at any temperature that facilitates optimal activity, typically between 4 and 40° C.

Direct binding of compounds to IR or IGF-1R can also be done by Surface Plasmon Resonance (BIAcore) (reviewed in Morton & Myszka, 1998). Here the receptor is immobilized on a CM5 or other sensor chip by either direct chemical coupling using amine or thiol-disulphide exchange coupling (Nice & Catimel, 1999) or by capturing the receptor ectodomain as an Fe fusion protein to an appropriately derivatised sensor surface (Morten & Myszka, 1998). The potential binding molecule (called an analyte) is passed over the sensor surface at an appropriate flow rate and a range of concentrations. The classical method of analysis is to collect responses for a wide range of analyte concentrations. A range of concentrations provides sufficient information about the reaction, and by using a fitting algorithm such as CLAMP (see Morton & Myszka, 1998), rate constants can be determined (Morton & Myszka, 1998; Nice & Catimel, 1999). Normally, the ligand surface is regenerated at the end of each analyte binding cycle. Surface regeneration ensures that the same number of ligand binding sites is accessible to the analyte at the beginning of each cycle.

Incubation periods are selected for optimum activity, but may also be optimized to facilitate rapid high-throughput screening. Normally, between 0.1 and 1 hour will be sufficient. In general, a plurality of assay mixtures is run in parallel with different test agent concentrations to obtain a differential response to these concentrations. Typically, one of these concentrations serves as a negative control, i.e. at zero concentration or below the level of detection.

The basic format of an in vitro competitive receptor binding assay as the basis of a heterogeneous screen for small organic molecular replacements for insulin may be as follows: occupation of the low affinity binding site of IR and/or IGF-1R is quantified by time-resolved fluorometric detection (TRFD) as described by Denley et al., 2004. R⁻IR-A, R⁻IR-B and P6 cells are used as sources of IR-A, IR-B and IGF-1R respectively. Cells are lysed with lysis buffer (20 mM HEPES, 150 mM NaCl, 1.5 mM MgCl₂, 10% (v/v) glycerol, 1% (v/v) Triton X-100, 1 mM EGTA pH 7.5) for 1 hour at 4° C. Lysates are centrifuged for 10 minutes at 3500 rpm and then 100 μl is added per well to a white Greiner Lumitrac 600 plate previously coated with anti-insulin receptor antibody 83-7 or anti-IGF-IR antibody 24-31. Neither capture antibody interferes with receptor binding by insulin, IGF-I or IGF-II. Approximately 100,000 fluorescent counts of europium-labelled insulin or europium-labelled IGF-I are added to each well along with various amounts of unlabelled competitor and incubated for 16 hours at 4° C. Wells are washed with 20 mM Tris, 150 mM NaCl, 0.05% (v/v) Tween 20 (TBST) and DELFIA enhancement solution (100 μl/well) is added. Time-resolved fluorescence is measured using 340 nm excitation and 612 nm emission filters with a BMG Lab Technologies Polarstar™ Fluorimeter or a Wallac Victor II (EG & G Wallac, Inc.).

Examples of other suitable assays which may be employed to assess the binding and biological activity of compounds to and on IR are well known in the art. For example, suitable assays may be found in PCT International Publication Number WO 03/027246. Examples of suitable assays include the following:

(i) Receptor autophosphorylation (as described by Denley et al., 2004). R⁻IR-A, R⁻IR-B cells or P6 cells are plated in a Falcon 96 well flat bottom plate at 2.5×10⁴ cells/well and grown overnight at 37° C., 5% CO₂. Cells are washed for 4 hours in serum-free medium before treating with one of either insulin, IGF-I or IGF-II in 100 μl DMEM with 1% BSA for 10 minutes at 37° C., 5% CO₂. Lysis buffer containing 2 mM Na₃VO₄ and 1 mg/ml NaF is added to cells and receptors from lysates are captured on 96 well plates precoated with antibody 83-7 or 24-31 and blocked with 1×TBST/0.5% BSA. After overnight incubation at 4° C., the plates are washed with 1×TBST. Phosphorylated receptor is detected with europium-labelled antiphosphotyrosine antibody PY20 (130 ng/well, room temperature, 2 hours). DELFIA enhancement solution (100 μl/well) is added and time resolved fluorescence detected as described above.

(ii) Glucose uptake using 2-deoxy-[U-14C] glucose (as described by Olefsky, 1978). Adipocytes between days 8-12 post-differentiation in 24-well plates are washed twice in Krebs-Ringer Bicarbonate Buffer (25 mM HEPES, pH 7.4 containing 130 mM NaCl, 5 mM KCl, KH₂PO₄, 1.3 mM MgSO₄.7H₂O, 25 mM NaHCO₃ and 1.15 mM CaCl₂) supplemented with 1% (w/v) RIA-grade BSA and 2 mM sodium pyruvate. Adipocytes are equilibrated for 90 min at 37° C. prior to insulin addition, or for 30 min prior to agonist or antagonist addition. Insulin (Actrapid, Novogen) is added over a concentration range of 0.7 to 70 nM for 30 min at 37° C. Agonist or antagonist (0 to 500 mM) is added to adipocytes for 90 min followed by the addition of insulin in the case of antagonists. Uptake of 50 mM 2-deoxy glucose and 0.5 mCi-2-deoxy-[U-¹⁴C] glucose (NEN, PerkinElmer Life Sciences) per well is measured over the final 10 min of agonist stimulation by scintillation counting.

(iii) Glucose transporter GLUT4 translocation using plasma membrane lawns (as described by Robinson & James (1992) and Marsh et al. (1995)).

(iv) GLUT4 translocation using plasma membrane lawns (as described by Marsh et al., 1995). 3T3-L1 fibroblasts are grown on glass coverslips in 6-well plates and differentiated into adipocytes. After 8-12 days post-differentiation, adipocytes are serum-starved for 18 hrs in DMEM containing 0.5% FBS. Cells are washed twice in Krebs-Ringer Bicarbonate Buffer, pH 7.4 and equilibrated for 90 min at 37° C. prior to insulin (100 nM) addition, or for 30 min prior to compound (100 μM) addition. After treatments, adipocytes are washed in 0.5 mg/ml poly-L-lysine in PBS, shocked hypotonically by three washes in 1:3 (v/v) membrane buffer (30 mM HEPES, pH 7.2 containing 70 mM KCl, 5 mM MgCl₂, 3 mM EGTA and freshly added 1 mM DTT and 2 mM PMSF) on ice. The washed cells are then sonicated using a probe sonicator (Microson) at setting 0 in 1:1 (v/v) membrane buffer on ice, to generate a lawn of plasma membrane fragments that remain attached to the coverslip. The fragments are fixed in 2% (w/v) paraformaldehyde in membrane buffer for 20 min at 22° C. and the fixative quenched by 100 mM glycine in PBS. The plasma membrane fragments are then blocked in 1% (w/v) Blotto in membrane buffer for 60 min at 22° C. and immunolabelled with an in-house rabbit affinity purified anti-GLUT4 polyclonal antibody (clone R10, generated against a peptide encompassing the C-terminal 19 amino acids of GLUT4) and Alexa 488 goat anti-rabbit secondary antibody (Molecular Probes; 1:200). Coverslips are mounted onto slides using FluoroSave reagent (Calbiochem), and imaged using an OptiScan confocal laser scanning immunofluoroscence microscope (Optiscan, VIC., Australia). Data are analysed using ImageJ (NIH) imaging software. At least six fields are examined within each experiment for each condition, and the confocal microscope gain settings over the period of experiments are maintained to minimise between-experiment variability.

Insulin agonist activity may be determined using an adipocyte assay. Insulin increases uptake of ³H glucose into adipocytes and its conversion into lipid. Incorporation of ³H into a lipid phase is determined by partitioning of lipid phase into a scintillant mixture, which excludes water-soluble ³H products. The effect of compounds on the incorporation of ³H glucose at a sub-maximal insulin dose is determined, and the results expressed as increase relative to full insulin response. The method is adapted from Moody et al., (1974). Mouse epididymal fat pads are dissected out, minced into digestion buffer (Krebs-Ringer 25 mM HEPES, 4% HSA, 1.1 mM glucose, 0.4 mg/ml Collagenase Type 1, pH 7.4), and digested for up to 1.5 hours at 36.5 C. After filtration, washing (Krebs-Ringer HEPES, 1% HSA) and resuspension in assay buffer (Krebs-Ringer HEPES, 1% HSA), free fat cells are pipetted into 96-well Picoplates containing test solution and approximately an ED₂₀ insulin.

The assay is started by addition of ³H glucose (e.g. ex. Amersham TRK 239), in a final concentration of 0.45 mM glucose. The assay is incubated for 2 hours at 36.5° C., in a Labshaker incubation tower, 400 rpm, then terminated by the addition of Permablend/Toluene scintillant (or equivalent), and the plates sealed before standing for at least 1 hour and detection in a Packard Top Counter or equivalent. A full insulin standard curve (8 dose) is run as control on each plate.

Data are presented graphically, as the effect of the compound on an (approximate) ED₂₀ insulin response, with data normalized to a full insulin response. The assay can also be run at basal or maximal insulin concentration.

To test the in vivo activity of a compound, an intravenous blood glucose test may be carried out on Wistar rats as follows. Male Mol:Wistar rats, weighing about 300 g, are divided into two groups. A 10 μl sample of blood is taken from the tail vein for determination of blood glucose concentration. The rats are then anaesthetized (e.g. with Hypnorm/Dormicum) at t=30 min and blood glucose measured again at t=−20 min and at t=0 min. After the t=0 sample is taken, the rats are injected into the tail vein with vehicle or test substance in an isotonic aqueous buffer at a concentration corresponding to a 1 ml/kg volume of injection. Blood glucose is measured at times 10, 20, 30, 40, 60, 80, 120 and 180 min. The anaesthetic administration is repeated at 20 min intervals.

Additional assays to determine the effect of binding molecules on IGF-1R activity are as follows:

(i) Cell Viability Assay on HT29 cells with induction of Apoptosis: The ability of compounds to inhibit IGF-mediated rescue from apoptosis is measured using the colorectal cell line HT29 cells (ATCC: HTB 38) after induction with Na Butyrate. The HT29 cells are plated out onto white Fluoronunc 96 well plates (Nunc) at 12,000 cells/ml and incubated at 37° C., 5% CO₂ for 48 hours. Media is aspirated and 100 μl/well of serum free DMEM/F12 is added for 2 hours to serum starve cells. IGF (100 μl/well 0.05-50 nM dilutions) in the presence and the absence of inhibitory compound is added in 0.1% BSA solution (Sigma) in DMEM/F12 (Gibco) in triplicate. A final concentration of 5 mM Butyrate (Sigma) is added to each well. Plates are incubated at 37° C., 5% CO₂ for a further 48 hours. Plates are brought to room temperature and developed (as per instructions for CTG Assay (Promega)). Luminescence signal is measured on the Polarstar plate reader and data is evaluated using table curve to obtain the specific ED50. (ii) Cell Migration Assay: The migration assays are performed in the modified 96-well Boyden chamber (Neuroprobe, Bethesda, Mass.). An 8 μM polycarbonate filter, which is pre-soaked in 25 μg/ml of collagen in 10 mM acetic acid overnight at 4° C., is placed so as to divide the chamber into an upper & lower compartment. Varying concentrations of the IGF-I analogues (25 μl of 0-100 nM) diluted in RPMI (Gibco) with 0.5% BSA (Sigma) tested for their migration including ability, are placed in the lower compartment in quadruplicates. The wells of the upper chamber are seeded with 50 μl/well of 2×10⁵ SW480 (ATCC:CCL 228) pre-incubated for 30 mins/37° C. with 1.1 μl of 2 μM Calcein (Molecular Probes). Cells migrate for 8 hours at 37° C., 5% CO₂. Unmigrated cells are removed by wiping the filter. The filter is then analysed in the Polarstar for fluorescence at excitation wavelength of 485 nm and emission wavelength of 520 nm. Data is evaluated using table curve to obtain the specific ED50 value. (iii) Mouse Xenograft studies for anti-IGF-1R antibodies: In vivo studies are performed in 56-week-old female athymic BALBc nude mice, homozygous for the nunu allele. Mice are maintained in autoclaved micro-isolator cages housed in a positive pressure containment rack (Thoren Caging Systems Inc., Hazelton, Pa., USA. To establish xenografts, mice are injected subcutaneously into the left inguinal mammary line with 3×10⁶ or 5×10⁶ cells in 100 μl of PBS. Tumour volume (TV) is calculated by the formula (length×width²)/2 (Clarke et al., 2000), where length is the longest axis and width the measurement at right angles to length.

Initial biodistribution of potential binding molecules are ascertained by injecting 40 BALBc nude mice with established xenografts with radiolabelled ¹¹¹In- or ¹²⁵I-anti-IGFR antibody (3 μg, 10 μCi) intravenously via the tail vein (total volume=0.1 ml). At designated time points after injection of the radioconjugates (t=4 h, days 1, 2, 3, 5 and 7), groups of mice (n=35) are killed by Ethrane anaesthesia. Mice are then exsanguinated by cardiac puncture, and tumours and organs (liver, spleen, kidney, muscle, skin, bone (femur), lungs, heart, stomach, brain, small bowel, tail and colon) are resected immediately. All samples are counted in a dual gamma scintillation counter (Packard Instruments). Triplicate standards prepared from the injected material are counted at each time point with tissue and tumour samples enabling calculations to be corrected for the physical decay of the isotopes. The tissue distribution data are calculated as the mean±s.d. percent injected dose per gram tissue (% ID g⁻¹) for the candidate molecule per time point.

Pharmacokinetics for the candidate compounds are ascertained as follows: Serum obtained from mice bearing xenografts, following infusion of radiolabelled-binding molecule as described above, is aliquoted in duplicate and counted in a gamma scintillation counter (Packard Instruments, Melbourne, Australia). Triplicate standards prepared from the injected material are counted at each time point with serum samples to enable calculations to be corrected for the isotope physical decay. The results of the serum are expressed as % injected dose per litre (% ID 1⁻¹). Pharmacokinetic calculations are performed of serum data using a curve fitting program (WinNonlin, Pharsight Co., Mountain View, Calif., USA). A two-compartment model is used to calculate serum pharmacokinetic parameters of AUC (area under the serum concentration curve extrapolated to infinite time), CL (total serum clearance), T_(12α) and T_(12β) (half-lives of the initial and terminal phases of disposition) for ¹²⁵I- and ¹¹¹In-labelled molecule

(iv) Therapeutic in vivo studies: Tumour cells (3×10⁶) in 100 μl of media are inoculated subcutaneously into both flanks of 46-week-old female nude mice (n=5 group⁻¹). Candidate molecule treatment commences day 7 post-tumour cell inoculations (mean±s.e. tumour volume=60×15 mm³) and consists of six intraperitoneal injections over 2 weeks of appropriate amounts of the candidate molecule or vehicle control. Tumour volume in mm³ is determined as described previously. Data is expressed as mean tumour volume for each treatment group. Differences in tumour size between control and test groups are tested for statistical significance (P<0.05) by t-test.

Uses of Compounds

Compounds/chemical entities designed or selected by the methods of the invention described above may be used to modulate IR and/or IGF-1R activity in cells, i.e., activate or inhibit IR and/or IGF-1R activity. Such compounds may interact with the low affinity binding sites of IR as defined herein, mimic the αCT segment of the α-chain of IR, or mimic insulin in complex with the IR as defined herein. They may also be used to modulate homodimerisation of IR and/or IGF-1R.

Modulation of homodimerisation of IR and/or IGF-1R may be achieved by direct binding of the chemical entity to a homodimerisation surface of IR and/or IGF-1R, and/or by an allosteric interaction elsewhere in the IR and/or IGF-1R extracellular domain.

Given that aberrant IR and/or IGF-1R activity is implicated in a range of disorders, the compounds described above may also be used to treat, ameliorate or prevent disorders characterised by abnormal IR and/or IGF-1R signalling. Examples of such disorders include malignant conditions including tumours of the brain, head and neck, prostate, ovary, breast, cervix, lung, pancreas and colon; and melanoma, rhabdomyosarcoma, mesothelioma, squamous carcinomas of the skin and glioblastoma.

The compounds designed to interact or identified as interacting with the extracellular domain of IR and/or IGF-1R, and in particular to interact with the target binding sites, are useful as agonists or antagonists against the action of insulin on IR and/or IGF on IGF-1R. The compounds are useful as assay reagents for identifying other useful ligands by, for example, competition assays, as research tools for further analysis of IR and/or IGF-1R and as potential therapeutics in pharmaceutical compositions.

Compounds provided by this invention are also useful as lead compounds for identifying other more potent or selective compounds. The mimetic compounds of the present invention are also potentially useful as inhibitors of the action of insulin and in the design of assay kits directed at identifying compounds capable of binding to the low affinity binding site for insulin on IR. The mimetic compounds of the present invention are also potentially useful as inhibitors of the action of IGF and in the design of assay kits directed at identifying compounds capable of binding to the low affinity binding site for IGF on IGF-1R. In particular, it is envisaged that compounds of the present invention will prove particularly useful in selecting/designing ligands which are specific for IR or IGF-1R.

In one embodiment, one or more of the compounds can be provided as components in a kit for identifying other ligands (e.g., small, organic molecules) that bind to IR or IGF-IR. Such kits may also comprise IR or IGF-IR, or functional fragments thereof. The compound and receptor components of the kit may be labelled (e.g., by radioisotopes, fluorescent molecules, chemiluminescent molecules, enzymes or other labels), or may be unlabeled and labelling reagents may be provided. The kits may also contain peripheral reagents such as buffers, stabilizers, etc. Instructions for use can also be provided.

IR and IGF-1R agonists and antagonists, and in particular antagonists, provided by this invention are potentially useful as therapeutics. For example, compounds are potentially useful as treatments for cancers, including, but not limited to, breast, prostate, colorectal, and ovarian cancers. Human and breast cancers are responsible for over 40,000 deaths per year, as present treatments such as surgery, chemotherapy, radiation therapy, and immunotherapy show limited success. Recent reports have shown that a previously identified IGF-1R antagonist can suppress retinal neovascularization, which causes diabetic retinopathy (Smith et al., 1999). IGF-1R agonist compounds (i.e. existing IGF-1R compounds which have been modified employing methods of the present invention) are useful for development as treatments for neurological disorders, including stroke and diabetic neuropathy. Reports of several different groups implicate IGF-1R in the reduction of global brain ischemia, and support the use of IGF-I for the treatment of diabetic neuropathy (reviewed in Auer et al., 1998; Apfel, 1999). A number of therapeutics directed against IGF-1R are currently undergoing clinical trial as anti-cancer agents (Hewish et al., 2009).

The IGF-1R agonist peptides of the invention may be useful for enhancing the survival of cells and/or blocking apoptosis in cells.

Administration

Compounds of the invention, i.e., ligands of the invention or modulators of IR and/or IGF-1R identified or identifiable by the screening methods of the invention, may preferably be combined with various components to produce compositions of the invention. Preferably the compositions are combined with a pharmaceutically acceptable carrier or diluent to produce a pharmaceutical composition (which may be for human or animal use).

The formulation will depend upon the nature of the compound and the route of administration but typically they can be formulated for, topical, parenteral, intramuscular, oral, intravenous, intra-peritoneal, intranasal inhalation, lung inhalation, intradermal or intra-articular administration. The compound may be used in an injectable form. It may therefore be mixed with any vehicle which is pharmaceutically acceptable for an injectable formulation, preferably for a direct injection at the site to be treated, although it may be administered systemically.

The pharmaceutically acceptable carrier or diluent may be, for example, sterile isotonic saline solutions, or other isotonic solutions such as phosphate-buffered saline. The compounds of the present invention may be admixed with any suitable binder(s), lubricant(s), suspending agent(s), coating agent(s), solubilising agent(s). It is also preferred to formulate the compound in an orally active form.

In general, a therapeutically effective daily oral or intravenous dose of the compounds of the invention, including compounds of the invention and their salts, is likely to range from 0.01 to 50 mg/kg body weight of the subject to be treated, preferably 0.1 to 20 mg/kg. The compounds of the invention and their salts may also be administered by intravenous infusion, at a dose which is likely to range from 0.001-10 mg/kg/hr.

Tablets or capsules of the compounds may be administered singly or two or more at a time, as appropriate. It is also possible to administer the compounds in sustained release formulations.

Typically, the physician will determine the actual dosage which will be most suitable for an individual patient and it will vary with the age, weight and response of the particular patient. The above dosages are exemplary of the average case. There can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.

For some applications, preferably the compositions are administered orally in the form of tablets containing excipients such as starch or lactose, or in capsules or ovules either alone or in admixture with excipients, or in the form of elixirs, solutions or suspensions containing flavouring or colouring agents.

The compositions (as well as the compounds alone) can also be injected parenterally, for example intravenously, intramuscularly or subcutaneously. In this case, the compositions will comprise a suitable carrier or diluent.

For parenteral administration, the compositions are best used in the form of a sterile aqueous solution which may contain other substances, for example enough salts or monosaccharides to make the solution isotonic with blood.

For buccal or sublingual administration the compositions may be administered in the form of tablets or lozenges which can be formulated in a conventional manner.

For oral, parenteral, buccal and sublingual administration to subjects (such as patients), the daily dosage level of the compounds of the present invention and their pharmaceutically acceptable salts and solvates may typically be from 10 to 500 mg (in single or divided doses). Thus, and by way of example, tablets or capsules may contain from 5 to 100 mg of active compound for administration singly, or two or more at a time, as appropriate. As indicated above, the physician will determine the actual dosage which will be most suitable for an individual patient and it will vary with the age, weight and response of the particular patient.

The routes of administration and dosages described are intended only as a guide since a skilled practitioner will be able to determine readily the optimum route of administration and dosage for any particular patient depending on, for example, the age, weight and condition of the patient.

EXAMPLES Experimental Procedures Crystallisation, Structure Solution and Refinement of IR310.T in Complex with Insulin Construction of the cIR485 Expression Vector

A 1741-base fragment of IR was synthesized (DNA2.0) and inserted into the HindIII/XbaI sites of the mammalian expression plasmid vector pEE14 (Bebbington & Hentschel, 1987). The fragment encoded a protein cIR485 (“cleavable” IR485; SEQ ID NO: 15) which consists, in order, of (i) the 27-residue IR native signal sequence, (ii) residues 1-310 of the IR α-chain (the L1-CR module), (iii) a thrombin cleavage site SSSLVPRGSSS, (iv) residues 311-485 of the IR α-chain (the L2 domain), (v) an enterokinase cleavage site DDDDK and (vi) a c-myc purification tag EQKLISEEDLN (Hoogenboom et al., 1991). A 106-base non-coding fragment GTCGACGGTACCCCGGGGAATTAATTCCGGGGGCCGCCTCGGAGCATGACCCCC GCGGGCCAGCGCCGCGCGCTCTGATCCGAGGAGACCCCGCGCTCCCGCAGCC was included between the Hind III site and the start codon; bases 29-106 of this fragment corresponding to those immediately upstream of the human IR coding region.

Cell Culture and Transfection

The expression plasmid pEE14/cIR485 was transfected into Lec8 mutant Chinese hamster ovary (CHO) cells (CRL-1737; ATCC) (Stanley, 1989) using LipofectAMINE 2000 (Life Technologies). The Lec8 cells were maintained in Dulbecco's Modified Eagle Medium: Nutrient Mixture F-12 (DMEM/F12; Life Technologies) containing 10% fetal bovine serum (FBS; Life Technologies). Transfected Lec8 cells were maintained in DMEM (High Glucose, Pyruvate, no Glutamine) plus 1× glutamine synthetase supplements (Sigma-Aldrich) and 10% dialyzed FBS (dFBS) containing 25 mM methionine sulphoximine (MSX, Sigma-Aldrich).

Transfectants from 96-well plates were screened for protein expression by Western blot with monoclonal antibodies 83-7 (Soos et al., 1986) and 9E10 (Evan et al., 1985). A high-yielding cell line was selected by screening a high number of transfectants.

Protein Production and Purification

The Lec8 host cell line containing the cIR485 construct was sub-cultured in tissue culture flasks initially and then in roller bottles (Greiner) for two weeks to prepare inocula for the spinner flasks. DMEM/F12 media supplemented with 10% dFBS and 25 μM MSX to maintain selection pressure was used during passaging and production work.

Cells from ten fully-confluent roller bottles were transferred to four spinner flasks (New Brunswick Scientific) containing Fibra-Cel disks (New Brunswick Scientific) to provide a matrix for cell attachment. Approximately 35×10⁷ viable cells/spinner flask were used to initiate production. The spinners were incubated in 5% CO₂ at 37° C. with 100 rpm stirring and ˜50 ml/min airflow. Spinner flasks were supplemented with 0.1% FoamAway (Life Technologies). Glucose and lactic acid levels were monitored daily, with spent media replaced to maintain residual glucose levels of ˜1.6 g/L.

The production phase lasted three weeks and ˜50 L of harvest collected, with the media being supplemented with 0.8 mM butyric acid (Sigma-Aldrich) during the last week.

Daily harvests from the spinners were kept at 4° C. after addition of 0.02% NaN₃ and 0.1 mM phenylmethanesulfonylfluoride (PMSF; Sigma-Aldrich). Pooled harvest batches were filtered with a 1.2/0.2μ filter to remover cell debris and concentrated approximately 10× using a 30 kDa cut-off membrane. All of the large-scale mammalian cell culture was performed under contract by CSIRO (Parkville, Australia).

Initial purification of cIR485 was by 9E10 antibody affinity chromatography and size-exclusion chromatography (SEC) using procedures effectively identical to those described for purification of IR485 (Lou et al., 2006).

Purified cIR485 in Tris-buffered saline (TBS; 24.8 mM Tris-HCl pH 8.0, 137 mM NaCl, 2.7 mM KCl) plus 0.02% sodium azide (TBSA) was then incubated overnight at 37° C. with 0.25 units human thrombin (Roche) per mg of cIR485 in the presence of 10 mM CaCl₂.

Completion of proteolysis was assessed by SDS-PAGE, which revealed bands corresponding to the estimated molecular weight of the IR310.T fragment and the IR L2 domain (51 kDa and 30 kDa, respectively; FIG. 5A).

Western blotting with Mab 83-7 (Soos et al., 1986) confirmed that the CR domain was contained in the upper band alone. The sample was diluted 8-fold in buffer A (10 mM ethanolamine-HCl, pH 9.6+0.02% sodium azide), centrifuged for 5 min at 17,000 g to remove particulates and then loaded onto MonoQ 5/50 GL column (GE Healthcare). The sample was eluted with a 60 column-volume gradient of buffer A to buffer B (10 mM ethanolamine-HCl, 400 mM NaCl, pH 9.6+0.02% sodium azide; FIG. 5B) and the fractions assessed by SDS-PAGE (FIG. 5A).

Fractions containing IR310.T (SEQ ID NO: 8) were pooled, concentrated and rerun in TBSA on a Superdex 200 10/300 column (GE Healthcare). The chromatogram exhibited three overlapping peaks, likely arising from multimerization (FIG. 5C).

SDS-PAGE of fractions revealed the presence of three closely-spaced bands, which we, attributed to varying glycosylation (FIG. 5D). Fractions containing IR310.T were pooled, concentrated and buffer exchanged into either TBSA or 10 mM HEPES-NaOH (pH 7.5)+0.02% NaN₃.

Mab 83-7 Production and Purification

A hybridoma cell line expressing Mab 83-7 (a gift from Prof. Ken Siddle, University of Cambridge, UK; SEQ ID NOs: 11 and 12) was then grown in large scale using Gibco Hybridoma Serum-free medium (H-SFM). Cells lines originally required 7-10% serum for optimal growth and 30-60 mg/l final yield.

A brief adaption experiment to lower serum levels was unsuccessful, at lower than 5% serum levels both viability and yield dropped.

The cells were then grown in 950 cm² roller bottles at 37° C., 5% CO₂ balanced with air and 10 rpm using approximately 300 ml H-SFM media supplemented with 5% fetal calf serum. Typically, 2-3 litres of cell culture at the viable cell density in the range of 2-3*10⁶ cells/ml was achieved. The cell culture was then pelleted (5 mins, 350 g) and re-suspended in serum-free medium. When cell viability dropped below 30% (after 5-7 days), the culture was harvested and the Mab 83-7 captured using a Protein-A column (Millipore). Under these conditions final yield was between 5-12 mg/l of cell culture medium.

Fab 83-7 Production and Purification

Production and purification of Fab 83-7 (SEQ ID NOs: 13 and 14) from Mab 83-7 was based on protocols described previously (McKern et al., 2006). Briefly, Mab 83-7 was digested with dithiothreitol-activated papain (Sigma-Aldrich) at 37° C. The digestion was stopped by adding iodoacetamide (IAA; Sigma-Aldrich), and the reaction mixture passed down a Superdex 200 26/60 column (GE Healthcare). Fractions containing 83-7 F(ab′)₂ were isolated and reduced with mercaptoethylamine (Sigma-Aldrich) and then alkylated with IAA, followed by further SEC and anion-exchange chromatography on Mono S (GE Healthcare).

IR310.T/Fab 83-7 Purification

IR310.T was mixed with a slight molar excess of Fab 83-7 and the complex purified by SEC using a S200 10/300 column (GE Healthcare) in TBSA buffer. Fractions containing the complex of IR310.T/Fab 83-7 were then pooled, concentrated and exchanged into 10 mM HEPES-NaOH (pH 7.5)+0.02% NaN₃.

Crystallization

Samples of the IR310.T/Fab 83-7 complex were prepared for crystallization by combining with a 1.5× molar ratio of αCT⁷⁰⁴⁻⁷¹⁹ (Genscript; SEQ ID NO: 9) and 3× molar ratio of human insulin (Sigma-Aldrich) to a final concentration of 3.5 mg/ml in 10 mM HEPES, pH 7.0. [D-Pro^(B26)]-DTI-NH₂ was prepared as described previously (Zakova et al., 2008).

A single crystallization condition (1.0 M trisodium citrate, 0.1 M imidazole HCl, pH 8.0+0.02% NaN₃) was detected for the IR310.T/Fab83-7/[D-Pro^(B26)]-DTI-NH₂/αCT⁷⁰⁴⁻⁷¹⁹ complex in a large (792-condition) sparse matrix sitting-drop screen set up in SBS-format sitting-drop plates, performed under contract by the CSIRO Collaborative Crystallization Centre (Parkville, Australia). This condition was refined manually for both [D-Pro^(B26)]-DTI-NH₂ and human insulin complexes within a range of 0.9-1.1 M trisodium citrate, 0.1 M imidazole HCl, pH 8.0+0.02% NaN₃ in hanging-drop plates. Crystals grew to a maximum size of 200-250 μm.

Diffraction Data Collection

Single crystals of the human insulin IR310.T quaternary complex were mounted in cryo-loops in paraffin oil HR403 (Hampton Research) and flash frozen in liquid nitrogen. Data Set 1 for IR310.T human insulin quaternary complex was collected (McPhillips et al., 2002) at the MX2 beamline at the Australian Synchrotron (Melbourne, Australia) using a Quantum 315 detector (ADSC). Data Set 2 was collected in similar fashion from a further crystal at beamline 124 at, the Diamond Light Source (Oxford, UK) using a Pilatus 6M detector (Dectris).

Crystals were transferred to reservoir solutions supplemented with 20% glycerol, flash frozen in liquid nitrogen and mounted directly on the MX2 beamline at the Australian Synchrotron. A number of crystals of 50-200 μm size were obtained, but only one diffracted to 4.4 Å, with the remainder diffracting to ˜6.0 Å Diffraction data were collected (McPhillips et al., 2002) from multiple volumes within the crystal in an endeavour to reduce the effects of radiation damage; however, only 88% completeness was achieved.

All diffraction data were processed using the XDS suite (Kabsch, 2010) and TRUNCATE within the CCP4 suite. Precision-indicating merging R factors (R_(pim)) were computed using SCALA within the CCP4 suite. Statistics for all data sets are provided in Table 2.

TABLE 2 X-ray data processing and refinement Data set 1 Data set 2 Data set 3 X-ray source Australian Diamond (combined Synchrotron Light Source Data sets 1 + 2) No. of frames 141 180 Oscillation range (°) 1.0 0.2 Exposure/frame (s)  3-15 0.2 Unit cell dimensions a = 168.15 Å a = 168.91 Å Space group P23 P23 Solvent content (%) 78 78 Data completeness (%) 99.8 (98.9)¹ 98.4 (99.6) 99.8 (99.7) Resolution (Å) 59.5-4.0  46.8-3.9  59.5-3.5  (4.1-4.0) (4.0-3.9) (3.6-3.5) R_(merge) 0.156 (2.33)²  0.089 (1.32)  0.216 (8.71)  CC^((1/2)) 0.998 (0.580)³ 0.998 (0.342) 0.998 (0.177) <I/s(I)> 11.46 (1.6)   8.95 (1.0)  9.32 (0.4)  Redundancy 17.3 (17.4)  4.1 (4.2) 23.8 (20.7) Protein atoms 4466 4466 Carbohydrate atoms 131 131 R_(work) 0.265⁴ 0.258 R_(free) (5% of refls) 0.293⁴ 0.279 s_(bond) (Å) 0.011 0.010 s_(angle) (°) 1.4 1.4 Ramachandran plot: favoured region (%) 90.9 90.8 acceptable region 5.1 5.8 (%) outliers (%) 4.0 3.8 ¹Numbers in parentheses refer to the statistic in the highest resolution shell. ²R_(merge) = Σ_(hkl)Σ_(i)|I_(i)(hkl) − <I(hkl)>|/Σ_(hkl)Σ_(i)I_(i)(hkl) ³CC^((1/2)) is the Pearson correlation coefficient between independently merged halves of the data set. Values for the highest resolution shell are significant at p = 0.001 and justify the use of data to the stated resolution (Karplus, 2012). ⁴R_(work) and R_(free) are computed using R = <|F_(h) ^(xpct) − F_(h) ^(obs)|>/<|F_(h) ^(obs)|> where F_(h) ^(xpct) is the expectation value of the model structure amplitude; Blanc et al., 2004).

Structure Solution and Refinement

Molecular replacement employed Data Set 1 (Table 2). A single copy of an L1-CR search fragment (residues 4-310, from PDB entry 3LOH) was located within the asymmetric unit using PHASER (TFZ=26.7) (McCoy, 2007). The variable module of Fab 83-7 (Fv, from PDB entry 3LOH) was then located in the presence of the L1-CR module (TFZ=37.6). Attempts to locate the Fab 83-7 constant module failed and it proved disordered. TLS parameters and individual isotropic B-factors for the L1-CR/Fv complex were then refined using autoBUSTER (Bricogne et al., 2011), followed by a subsequent atomic coordinate-only refinement, yielding R^(xpct) _(work)/R^(xpct) _(free)=0.368/0.363, where “xpct” denotes the statistic's expectation value (Blanc et al., 2004). The resultant difference density maps revealed tubular helix-like features (the 1^(st), 3^(rd), 4^(th), 5^(th) and 7^(th) highest peaks within the map) in the immediate vicinity of the L1-β₂ surface, into which PHASER unambiguously positioned a rigid model comprising the three insulin helices (TFZ=11.4). The correctness of this solution was confirmed by an exhaustive 6-dimensional real-space search using ESSENS (Kleywegt and Jones, 1997) to locate the core fragment within the F_(o)-F_(c) map. The ESSENS search, refined on a (1°, 0.33 Å) grid, yielded a single solution, with a Z-score of 12.6 and an rmsd of 0.7 Å from that obtained by PHASER. The 2^(nd) highest difference electron density feature corresponded to glycan attached to Asn111 (FIG. 6A), configured effectively identically to its counterpart in the structure of uncomplexed IR485 (Lou et al., 2006). The L1-CR/Fv/insulin core model was then refined further, yielding R^(xpct) _(work)/R^(xpct) _(free)=0.320/0.339.

The remaining helix-like feature in the above difference map (encompassing the 1^(st) and 5^(th) highest peaks) revealed clear side chain protrusions upon B-factor map sharpening, spaced consistent with an underlying α-helix (FIG. 6B). We concluded that the feature arose from the αCT peptide. A 10-residue polyalanine α-helix was docked into this feature using an ESSENS search with all constituent atoms contributing to the target function to allow discernment of helix direction. The best fit had Z-score of 7.3 and was adequately discriminated from lower-scoring fits. Visual inspection confirmed the overall correctness of the fit to the density and, in particular, the direction of the helix as judged by protruding side-chain density.

Register assignment of the αCT⁷⁰⁴⁻⁷¹⁹ sequence to the decameric polyalanine helix was achieved using a procedure that assessed both compatibility of individual residue side chains with difference electron density and compatibility of individual residue side chains with their surrounding protein environment. (a) Fit to difference density employed the following method that was designed not only to assess the fit of atoms within the density, but also to penalize the existence of volumes of positive difference density into which no atoms had been placed. Briefly, the map feature assigned to the αCT segment was excised from the B-factor sharpened map using CHIMERA (Pettersen et al., 2004) (cut-off level=0.16 e⁻/A³) and placed within a rectangular grid volume large enough to allow a >8 Å buffer zone around the αCT feature. All grid points outside of the feature were set to 0 e/Å³, with the resultant map being termed M_(obs). Coordinates for residues 1, 2 and 10 of the fitted polyalanine helix were then deleted from the model, as the density associated with them displayed somewhat poorer α-helical geometry. Ten comparisons corresponding to all possible alignments of heptameric sequences from αCT⁷⁰⁴⁻⁷¹⁹ with the heptameric polyalanine structure were considered. Rotamers for each residue within each of these ten models were then selected manually using COOT (Emsley and Cowtan, 2004) based on visual inspection of the fit of the trial rotamer to the density at the corresponding site in M_(obs). The ten individual models were then “real-space-refined” within COOT to achieve optimal fit to M_(obs), maintaining tight helical restraints. An electron density map M_(calc), on the same grid as M_(obs) was then generated (using SFALL within CCP4) for each heptamer model in isolation, with the B-factors of all main-chain atoms being set to 10 Å² and of all side-chain atoms set to 20 Å² to allow for subsequent comparison with a sharpened map. All density within M_(calc) lower than 0.45 e⁻/A³ was set to 0 e⁻/A³. Correlation coefficients CC=(<xy>−<x><y>)/√[(<x2>−<x>²) (<y²>−<y>²)] between M_(obs) and each M_(calc) were then calculated using MAPMAN (Jones and Thirup, 1986). Each CC was then “normalized” by dividing its value by the CC value calculated for the underlying polyalanine heptamer, and the quotient termed the trial sequence's “density score”. Trial register 705-711 was seen to have the highest density score (Table 3). (b) Compatibility of residue side-chain environment within the putative L1/αCT/insulin interface was assessed as follows. For each of the ten trial heptamer (real-space refined) models described above, an environment score was generated using VERIFY3D (Luthy et al., 1992) in order to assess compatibility with the surrounding L1-β₂ and insulin surfaces. Trial register 705-711 again scored highest (Table 3). A “combined score” was then computed as the product (density score)×(environment score) in order to assist with assessing lower ranked trial registers (Table 3). The next highest combined score was for trial register 709-715, which is related trial register 705-711 by a one-turn translation along the helix, effectively maintaining hydrophobic-to-hydrophobic docking with the L1 surface. However, register 709-715 was judged to be most unlikely, as it would bring Pro716 and Pro718 into the remaining C-terminal part of the overall helix. We thus concluded that register assignment 705-711 was correct, given that it was the highest ranking on all criteria. The assignment was subsequently confirmed by the structure determination of the insulin-complexed IR593.αCT construct, which has the segment directly and covalently attached to the C-terminus of FnIII-1.

TABLE 3 Density and environmental fit scores for various trial αCT registers, indicating the consistently high score assigned to register 705-711. IR αCT register Density fit score¹ Environment fit score² Combined score³ 704-710 1.13 11.3 12.8 705-711 1.15 ⁴ 18.5 21.3 706-712 1.11 13.4 14.9 707-713 1.13 13.8 15.6 708-714 1.03 15.4 15.9 709-715 1.13 16.9 19.0 710-716 1.06 14.4 15.2 711-717 1.06 14.4 15.2 712-718 1.04 12.0 12.5 713-719 1.04  8.19  8.5 ¹Density score = (Correlation of the computed electron density for the trial IR αCT heptamer with the difference electron density feature shown in FIG. 6B)/(Correlation of the computed electron density for the initial polyalanine heptamer with the difference electron density feature shown in FIG. 6B). ²Environment fit score computed using VERIFY3D (Luthy et al., 1992). ³Combined score = (density fit score) × (environment fit score). ⁴Highest scores within each column are underlined.

The 705-711 peptide model was then included in the insulin/IR310.T/Fab83-7 atomic model and autoBUSTER refinement continued against Data Set 2, which became available in the interim (Table 2, assigned identical free-R set to Data Set 1). Residues 712-715 were built as a further α-helical turn beyond residue 711 and a total of nine sugars added at sites 16, 25, 111, 225 and 255 (Lou et al., 2006; Sparrow et al., 2008), followed by iterative rounds of refinement and model rebuilding (COOT). LSSR restraints to higher-resolution structures (Smart et al., 2012) were included for IR310.T (restrained to PDB entry 2HR7-A) and the Fab83-7 light chain (to PDB entry 11L1-B) and heavy chain (to PDB entry 1FNS-C). Final refinement statistics are detailed in Table 2. Inclusion of data to 3.9 Å was justified a posteriori—the average figure of merit for free set reflections remained above 0.70 at this limit.

Extension of Resolution to 3.5 Å and Model Building

Data sets 1 and 2 for the human insulin complexed IR310.T/83-7/αCT⁷⁰⁴⁻⁷¹⁹ crystal were then re-processed to extended resolution of 3.5 Å, based on a recent report that additional information could be obtained by inclusion of weak data at the very limit of diffraction. The integrated reflection data from the two sets were then scaled and merged together, the combined data set having CC^((1/2))=0.998, significant at the p=0.001 level of confidence.

The prior model of human insulin complexed IR310.T/83-7/αCT⁷⁰⁴⁻⁷¹⁹ refined at 3.9 Å resolution against Data set 2 was then re-refined against this extended resolution data set using autoBUSTER.

Examination of the resultant difference density maps showed that insulin residue A21 was misplaced in the earlier refinement. This residue was then removed from model and the model re-refined. The resultant difference maps revealed that residues B21-B24 could be built in a near native-like conformation, with the side chain of residue B24 directed into a hydrophobic pocket formed by the side chains of residues Phe714, Phe39, Leu37 and LeuB15. We then observed that residues PheB25 and TyrB26 could be built into difference electron density, in a non-native like fashion with the side chain of residue TyrB25 directed towards the αCT peptide in the vicinity of residue Val715 and the side chain of residue TyrB26 directed towards L1 domain residues Asn12 and Arg19.

Val715 was then removed from the model to avoid steric clash with TyrB25. We noted that Val715 is replaced by glutamate in some insulin receptors, incompatible with it being directed towards the L1 surface in the fashion prescribed by the lower resolution model and hence it like A21 had been built incorrectly in the lower resolution model.

A number of rounds of model building then followed using autoBUSTER, with the loop B20-B23 restrained to a native-like conformation. The resultant model showed a good fit to the electron density and a reduced R/R_(free) with respect to the starting structure.

Example 1 A Thermodynamic Study of Insulin Binding to IR310.T Introduction

In order to assess insulin binding to IR310.T in the presence of Fab 83.7 isothermal titration calorimetry (“ITC”) was used. ITC allowed a direct assay of the interactions between the construct IR310.T (described above) complexed with Fab 83.7 and zinc free human insulin and between the construct IR310.T (not complexed with Fab 83.7) and zinc free human insulin. All interactions were assayed in presence of a 10× molar ratio of αCT⁷⁰⁴⁻⁷¹⁹.

Reagents

Protocols and instrumentation for ITC determination of the thermodynamic parameters of binding of (a) zinc-free porcine insulin to a pre-formed complex of IR310.T and αCT⁷⁰⁴⁻⁷¹⁹, (b) zinc-free porcine insulin to a pre-formed complex of IR310.T/Fab83-7 and αCT⁷⁰⁴⁻⁷¹⁹, (c) alanine-substituted αCT peptide to the L1-CR-L2 construct IR485 and (d) zinc-free porcine insulin to a pre-formed complex of alanine-substituted αCT⁷⁰⁴⁻⁷¹⁹ and IR485 were identical to those described previously (Menting et al., 2009).

Briefly, all experiments were conducted using a VP-ITC isothermal titration calorimeter (MicroCal) with the calorimeter cell held at 25° C. All samples were degassed prior to injection or placement into the cell, and the instrument was temperature-equilibrated prior to the start of the injections. In all experiments, the volume of the sample placed in the cell was 1.4 ml and the titrant was injected in 7 μl volumes over 14 s at 3 min intervals, with the total number of injections being 40. The sample contents were stirred at a speed of 310 rpm over the duration of the titration. For peptide titrations, the titrant was prepared at 80 μM in TBSA, with the sample cell holding IR485 at 10 μM concentration. For insulin and insulin analogue titrations, the titrant was prepared at 32 to 48 μM concentration in TBSA with the sample cell containing IR485 at 4 to 6 μM concentration in TBSA and pre-incubated with a 10× molar ratio of the respective Ala-substituted αCT peptide. Data were analysed using the instrument's software and in all cases fitted as a single-site interaction. All measurements were performed in triplicate.

Results

ITC analysis showed that zinc-free human insulin bound IR310.T with K_(d)=30 nM in the presence of a 10× molar ratio of αCT⁷⁰⁴⁻⁷¹⁹ (FIG. 5E), and that zinc-free human insulin bound Fab 83-7 complexed IR310.T with K_(d)=48 nM in the presence of a 10× molar ratio of αCT⁷⁰⁴⁻⁷¹⁹ (FIG. 5F).

The disclosure of all publications referred to in this application are incorporated herein by reference.

In compliance with the statute, the invention has been described in language more or less specific to structural or methodical features. It is to be understood that the invention is not limited to specific features shown or described since the means herein described comprises preferred forms of putting the invention into effect. The invention is, therefore, claimed in any of its forms or modifications within the proper scope of the appended claims (if any) appropriately interpreted by those skilled in the art.

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APPENDIX I ATOMIC COORDINATES FOR IR310.T MONOMER (CHAIN E) WITH ATTACHED αCT PEPTIDE (CHAIN F), HUMAN INSULIN MONOMER (CHAINS A AND B) AND Fab 83-7 (CHAINS C AND D) ATOM 1 N GLY A 1 31.737 −47.052 −15.556 1.00 186.71 ATOM 2 CA GLY A 1 32.951 −46.963 −16.365 1.00 186.36 ATOM 3 C GLY A 1 32.828 −45.909 −17.446 1.00 189.75 ATOM 4 O GLY A 1 32.585 −44.748 −17.129 1.00 188.96 ATOM 5 N ILE A 2 32.937 −46.314 −18.736 1.00 186.15 ATOM 6 CA ILE A 2 32.787 −45.454 −19.928 1.00 185.79 ATOM 7 C ILE A 2 31.534 −44.590 −19.816 1.00 192.27 ATOM 8 O ILE A 2 31.519 −43.475 −20.317 1.00 191.57 ATOM 9 CB ILE A 2 32.769 −46.301 −21.241 1.00 187.88 ATOM 10 CG1 ILE A 2 32.843 −45.406 −22.494 1.00 187.01 ATOM 11 CG2 ILE A 2 31.584 −47.311 −21.287 1.00 188.88 ATOM 12 CD1 ILE A 2 32.317 −45.992 −23.743 1.00 186.23 ATOM 13 N VAL A 3 30.499 −45.132 −19.149 1.00 192.14 ATOM 14 CA VAL A 3 29.171 −44.566 −18.879 1.00 194.24 ATOM 15 C VAL A 3 29.234 −43.566 −17.742 1.00 202.11 ATOM 16 O VAL A 3 28.583 −42.518 −17.789 1.00 201.42 ATOM 17 CB VAL A 3 28.188 −45.721 −18.532 1.00 198.80 ATOM 18 CG1 VAL A 3 26.795 −45.215 −18.126 1.00 198.93 ATOM 19 CG2 VAL A 3 28.100 −46.716 −19.681 1.00 198.25 ATOM 20 N GLU A 4 29.974 −43.922 −16.696 1.00 202.33 ATOM 21 CA GLU A 4 30.086 −43.072 −15.525 1.00 204.40 ATOM 22 C GLU A 4 31.245 −42.072 −15.608 1.00 208.87 ATOM 23 O GLU A 4 31.227 −41.080 −14.882 1.00 208.80 ATOM 24 CB GLU A 4 30.025 −43.906 −14.225 1.00 206.53 ATOM 25 CG GLU A 4 28.728 −44.707 −14.074 1.00 221.10 ATOM 26 CD GLU A 4 27.428 −43.914 −14.123 1.00 253.39 ATOM 27 OE1 GLU A 4 26.930 −43.519 −13.044 1.00 256.12 ATOM 28 OE2 GLU A 4 26.901 −43.693 −15.238 1.00 250.04 ATOM 29 N GLN A 5 32.181 −42.292 −16.568 1.00 205.56 ATOM 30 CA GLN A 5 33.376 −41.488 −16.876 1.00 205.86 ATOM 31 C GLN A 5 33.108 −40.479 −18.011 1.00 211.44 ATOM 32 O GLN A 5 33.743 −39.421 −18.034 1.00 211.70 ATOM 33 CB GLN A 5 34.543 −42.437 −17.233 1.00 206.26 ATOM 34 CG GLN A 5 35.846 −41.828 −17.753 1.00 209.80 ATOM 35 CD GLN A 5 36.640 −42.888 −18.483 1.00 223.23 ATOM 36 OE1 GLN A 5 36.089 −43.691 −19.238 1.00 217.40 ATOM 37 NE2 GLN A 5 37.951 −42.935 −18.272 1.00 214.35 ATOM 38 N CYS A 6 32.180 −40.809 −18.945 1.00 208.45 ATOM 39 CA CYS A 6 31.843 −39.957 −20.089 1.00 208.46 ATOM 40 C CYS A 6 30.379 −39.501 −20.183 1.00 211.68 ATOM 41 O CYS A 6 30.099 −38.573 −20.944 1.00 209.81 ATOM 42 CB CYS A 6 32.367 −40.536 −21.400 1.00 208.91 ATOM 43 SG CYS A 6 34.063 −41.190 −21.302 1.00 213.56 ATOM 44 N CYS A 7 29.466 −40.075 −19.357 1.00 210.76 ATOM 45 CA CYS A 7 28.081 −39.600 −19.303 1.00 212.79 ATOM 46 C CYS A 7 27.757 −38.804 −18.059 1.00 219.11 ATOM 47 O CYS A 7 27.671 −37.575 −18.168 1.00 219.63 ATOM 48 CB CYS A 7 27.037 −40.668 −19.605 1.00 213.87 ATOM 49 SG CYS A 7 25.876 −40.195 −20.921 1.00 218.12 ATOM 50 N THR A 8 27.621 −39.457 −16.876 1.00 217.02 ATOM 51 CA THR A 8 27.404 −38.715 −15.619 1.00 218.63 ATOM 52 C THR A 8 28.618 −37.768 −15.488 1.00 223.50 ATOM 53 O THR A 8 28.441 −36.547 −15.595 1.00 223.51 ATOM 54 CB THR A 8 27.128 −39.639 −14.401 1.00 225.58 ATOM 55 OG1 THR A 8 28.312 −40.357 −14.045 1.00 226.59 ATOM 56 CG2 THR A 8 25.932 −40.589 −14.613 1.00 219.68 ATOM 57 N SER A 9 29.853 −38.344 −15.435 1.00 220.28 ATOM 58 CA SER A 9 31.123 −37.593 −15.481 1.00 220.67 ATOM 59 C SER A 9 31.389 −37.222 −16.970 1.00 223.32 ATOM 60 O SER A 9 30.848 −37.895 −17.850 1.00 222.92 ATOM 61 CB SER A 9 32.274 −38.407 −14.880 1.00 224.27 ATOM 62 OG SER A 9 33.525 −38.269 −15.542 1.00 233.29 ATOM 63 N ILE A 10 32.173 −36.141 −17.252 1.00 217.80 ATOM 64 CA ILE A 10 32.424 −35.684 −18.632 1.00 215.17 ATOM 65 C ILE A 10 33.838 −36.044 −19.173 1.00 215.54 ATOM 66 O ILE A 10 34.839 −35.982 −18.453 1.00 214.66 ATOM 67 CB ILE A 10 31.873 −34.241 −18.922 1.00 218.28 ATOM 68 CG1 ILE A 10 30.383 −34.014 −18.378 1.00 218.40 ATOM 69 CG2 ILE A 10 32.037 −33.829 −20.394 1.00 218.12 ATOM 70 CD1 ILE A 10 29.056 −34.647 −19.169 1.00 214.17 ATOM 71 N CYS A 11 33.866 −36.501 −20.431 1.00 210.74 ATOM 72 CA CYS A 11 35.005 −37.064 −21.155 1.00 210.30 ATOM 73 C CYS A 11 35.909 −36.089 −21.888 1.00 212.63 ATOM 74 O CYS A 11 35.448 −35.239 −22.657 1.00 210.85 ATOM 75 CB CYS A 11 34.518 −38.170 −22.095 1.00 210.31 ATOM 76 SG CYS A 11 35.393 −39.762 −21.944 1.00 214.15 ATOM 77 N SER A 12 37.218 −36.288 −21.690 1.00 209.84 ATOM 78 CA SER A 12 38.304 −35.593 −22.382 1.00 209.99 ATOM 79 C SER A 12 38.610 −36.502 −23.563 1.00 211.83 ATOM 80 O SER A 12 38.563 −37.725 −23.400 1.00 211.06 ATOM 81 CB SER A 12 39.528 −35.467 −21.471 1.00 214.68 ATOM 82 OG SER A 12 40.761 −35.834 −22.075 1.00 223.54 ATOM 83 N LEU A 13 38.933 −35.932 −24.735 1.00 207.24 ATOM 84 CA LEU A 13 39.213 −36.730 −25.931 1.00 206.83 ATOM 85 C LEU A 13 40.276 −37.829 −25.792 1.00 209.14 ATOM 86 O LEU A 13 40.432 −38.666 −26.695 1.00 207.43 ATOM 87 CB LEU A 13 39.425 −35.859 −27.166 1.00 207.56 ATOM 88 CG LEU A 13 38.707 −36.307 −28.442 1.00 212.48 ATOM 89 CD1 LEU A 13 37.217 −35.965 −28.391 1.00 211.59 ATOM 90 CD2 LEU A 13 39.370 −35.704 −29.684 1.00 216.13 ATOM 91 N TYR A 14 40.965 −37.863 −24.637 1.00 206.66 ATOM 92 CA TYR A 14 41.901 −38.941 −24.375 1.00 207.15 ATOM 93 C TYR A 14 41.134 −40.151 −23.869 1.00 209.90 ATOM 94 O TYR A 14 41.283 −41.234 −24.434 1.00 209.79 ATOM 95 CB TYR A 14 43.016 −38.603 −23.369 1.00 209.13 ATOM 96 CG TYR A 14 43.706 −39.890 −22.968 1.00 211.84 ATOM 97 CD1 TYR A 14 44.316 −40.702 −23.927 1.00 214.41 ATOM 98 CD2 TYR A 14 43.596 −40.389 −21.671 1.00 212.97 ATOM 99 CE1 TYR A 14 44.839 −41.953 −23.598 1.00 216.03 ATOM 100 CE2 TYR A 14 44.149 −41.627 −21.321 1.00 214.39 ATOM 101 CZ TYR A 14 44.774 −42.406 −22.291 1.00 222.21 ATOM 102 OH TYR A 14 45.342 −43.630 −21.992 1.00 220.55 ATOM 103 N GLN A 15 40.378 −39.991 −22.759 1.00 204.72 ATOM 104 CA GLN A 15 39.613 −41.076 −22.142 1.00 203.03 ATOM 105 C GLN A 15 38.930 −41.983 −23.154 1.00 203.72 ATOM 106 O GLN A 15 38.768 −43.159 −22.873 1.00 202.89 ATOM 107 CB GLN A 15 38.636 −40.559 −21.087 1.00 204.31 ATOM 108 CG GLN A 15 39.304 −40.122 −19.787 1.00 216.06 ATOM 109 CD GLN A 15 39.279 −38.628 −19.606 1.00 225.02 ATOM 110 OE1 GLN A 15 38.208 −37.987 −19.579 1.00 213.61 ATOM 111 NE2 GLN A 15 40.466 −38.055 −19.419 1.00 217.98 ATOM 112 N LEU A 16 38.607 −41.451 −24.354 1.00 198.95 ATOM 113 CA LEU A 16 38.038 −42.196 −25.477 1.00 197.96 ATOM 114 C LEU A 16 39.107 −42.912 −26.366 1.00 204.30 ATOM 115 O LEU A 16 38.754 −43.904 −27.017 1.00 203.61 ATOM 116 CB LEU A 16 37.060 −41.355 −26.319 1.00 196.58 ATOM 117 CG LEU A 16 35.753 −40.931 −25.677 1.00 198.33 ATOM 118 CD1 LEU A 16 35.860 −39.537 −25.192 1.00 198.12 ATOM 119 CD2 LEU A 16 34.644 −40.937 −26.691 1.00 197.87 ATOM 120 N GLU A 17 40.393 −42.436 −26.396 1.00 203.04 ATOM 121 CA GLU A 17 41.464 −43.149 −27.119 1.00 204.91 ATOM 122 C GLU A 17 41.527 −44.494 −26.429 1.00 213.93 ATOM 123 O GLU A 17 41.495 −45.522 −27.106 1.00 215.72 ATOM 124 CB GLU A 17 42.862 −42.487 −26.970 1.00 206.66 ATOM 125 CG GLU A 17 44.060 −43.342 −27.439 1.00 214.83 ATOM 126 CD GLU A 17 44.520 −44.611 −26.709 1.00 224.64 ATOM 127 OE1 GLU A 17 44.942 −44.529 −25.530 1.00 203.51 ATOM 128 OE2 GLU A 17 44.513 −45.688 −27.352 1.00 212.80 ATOM 129 N ASN A 18 41.650 −44.471 −25.069 1.00 211.20 ATOM 130 CA ASN A 18 41.753 −45.620 −24.171 1.00 211.23 ATOM 131 C ASN A 18 41.284 −46.928 −24.816 1.00 216.76 ATOM 132 O ASN A 18 42.113 −47.819 −25.070 1.00 217.67 ATOM 133 CB ASN A 18 40.932 −45.362 −22.897 1.00 210.56 ATOM 134 CG ASN A 18 41.619 −44.591 −21.804 1.00 230.65 ATOM 135 OD1 ASN A 18 42.829 −44.709 −21.603 1.00 228.38 ATOM 136 ND2 ASN A 18 40.838 −43.885 −20.988 1.00 218.23 ATOM 137 N TYR A 19 39.954 −46.963 −25.170 1.00 212.26 ATOM 138 CA TYR A 19 39.116 −48.065 −25.681 1.00 211.48 ATOM 139 C TYR A 19 39.274 −48.525 −27.145 1.00 214.08 ATOM 140 O TYR A 19 38.342 −49.153 −27.669 1.00 213.48 ATOM 141 CB TYR A 19 37.636 −47.728 −25.434 1.00 211.91 ATOM 142 CG TYR A 19 37.307 −47.248 −24.041 1.00 214.04 ATOM 143 CD1 TYR A 19 37.361 −48.116 −22.951 1.00 216.92 ATOM 144 CD2 TYR A 19 36.841 −45.956 −23.822 1.00 214.35 ATOM 145 CE1 TYR A 19 37.009 −47.692 −21.669 1.00 218.74 ATOM 146 CE2 TYR A 19 36.477 −45.523 −22.548 1.00 215.16 ATOM 147 CZ TYR A 19 36.566 −46.392 −21.473 1.00 224.76 ATOM 148 OH TYR A 19 36.208 −45.965 −20.219 1.00 226.93 ATOM 149 N CYS A 20 40.433 −48.271 −27.794 1.00 209.85 ATOM 150 CA CYS A 20 40.578 −48.616 −29.210 1.00 214.12 ATOM 151 C CYS A 20 41.666 −49.637 −29.665 1.00 210.58 ATOM 152 O CYS A 20 42.766 −49.736 −29.116 1.00 156.27 ATOM 153 CB CYS A 20 40.556 −47.359 −30.079 1.00 214.21 ATOM 154 SG CYS A 20 39.473 −46.029 −29.464 1.00 216.29 ATOM 156 N CYS B 7 23.960 −38.221 −23.082 1.00 232.97 ATOM 157 CA CYS B 7 25.056 −38.561 −24.003 1.00 229.98 ATOM 158 C CYS B 7 24.970 −40.015 −24.562 1.00 225.15 ATOM 159 O CYS B 7 25.917 −40.482 −25.206 1.00 222.28 ATOM 160 CB CYS B 7 26.417 −38.269 −23.364 1.00 231.56 ATOM 161 SG CYS B 7 27.143 −39.672 −22.458 1.00 235.21 ATOM 162 N GLY B 8 23.830 −40.676 −24.313 1.00 217.38 ATOM 163 CA GLY B 8 23.520 −42.044 −24.709 1.00 213.28 ATOM 164 C GLY B 8 24.120 −42.490 −26.023 1.00 210.24 ATOM 165 O GLY B 8 25.270 −42.944 −26.052 1.00 208.44 ATOM 166 N SER B 9 23.348 −42.341 −27.124 1.00 202.95 ATOM 167 CA SER B 9 23.744 −42.737 −28.486 1.00 199.17 ATOM 168 C SER B 9 25.045 −42.082 −28.921 1.00 198.52 ATOM 169 O SER B 9 25.894 −42.739 −29.522 1.00 195.47 ATOM 170 CB SER B 9 22.629 −42.431 −29.489 1.00 202.12 ATOM 171 OG SER B 9 22.321 −41.050 −29.598 1.00 207.98 ATOM 172 N HIS B 10 25.189 −40.781 −28.565 1.00 194.66 ATOM 173 CA HIS B 10 26.294 −39.852 −28.847 1.00 192.96 ATOM 174 C HIS B 10 27.662 −40.379 −28.406 1.00 192.77 ATOM 175 O HIS B 10 28.654 −40.128 −29.088 1.00 190.71 ATOM 176 CB HIS B 10 25.995 −38.448 −28.265 1.00 195.43 ATOM 177 CG HIS B 10 24.532 −38.075 −28.241 1.00 200.51 ATOM 178 ND1 HIS B 10 23.642 −38.518 −29.220 1.00 201.87 ATOM 179 CD2 HIS B 10 23.849 −37.316 −27.351 1.00 204.64 ATOM 180 CE1 HIS B 10 22.458 −38.029 −28.882 1.00 203.13 ATOM 181 NE2 HIS B 10 22.530 −37.301 −27.766 1.00 205.30 ATOM 182 N LEU B 11 27.706 −41.147 −27.298 1.00 187.77 ATOM 183 CA LEU B 11 28.940 −41.761 −26.811 1.00 185.44 ATOM 184 C LEU B 11 29.329 −42.880 −27.747 1.00 185.19 ATOM 185 O LEU B 11 30.527 −43.088 −27.958 1.00 182.23 ATOM 186 CB LEU B 11 28.805 −42.254 −25.354 1.00 185.86 ATOM 187 CG LEU B 11 29.952 −43.090 −24.734 1.00 189.01 ATOM 188 CD1 LEU B 11 31.332 −42.458 −24.932 1.00 188.16 ATOM 189 CD2 LEU B 11 29.704 −43.316 −23.272 1.00 193.32 ATOM 190 N VAL B 12 28.325 −43.585 −28.338 1.00 182.38 ATOM 191 CA VAL B 12 28.645 −44.640 −29.308 1.00 181.99 ATOM 192 C VAL B 12 29.279 −43.915 −30.501 1.00 187.02 ATOM 193 O VAL B 12 30.314 −44.368 −30.998 1.00 188.18 ATOM 194 CB VAL B 12 27.514 −45.642 −29.754 1.00 185.60 ATOM 195 CG1 VAL B 12 28.107 −46.995 −30.137 1.00 183.94 ATOM 196 CG2 VAL B 12 26.427 −45.827 −28.699 1.00 186.32 ATOM 197 N GLU B 13 28.723 −42.736 −30.878 1.00 181.73 ATOM 198 CA GLU B 13 29.219 −41.943 −31.998 1.00 180.32 ATOM 199 C GLU B 13 30.543 −41.230 −31.732 1.00 182.27 ATOM 200 O GLU B 13 31.435 −41.334 −32.578 1.00 181.29 ATOM 201 CB GLU B 13 28.122 −41.050 −32.570 1.00 182.32 ATOM 202 CG GLU B 13 27.083 −41.867 −33.323 1.00 194.34 ATOM 203 CD GLU B 13 25.640 −41.400 −33.250 1.00 230.28 ATOM 204 OE1 GLU B 13 25.396 −40.169 −33.238 1.00 226.43 ATOM 205 OE2 GLU B 13 24.747 −42.280 −33.248 1.00 233.16 ATOM 206 N ALA B 14 30.702 −40.584 −30.535 1.00 178.12 ATOM 207 CA ALA B 14 31.936 −39.909 −30.086 1.00 177.54 ATOM 208 C ALA B 14 33.097 −40.906 −30.140 1.00 182.19 ATOM 209 O ALA B 14 34.128 −40.608 −30.735 1.00 179.92 ATOM 210 CB ALA B 14 31.768 −39.363 −28.669 1.00 178.72 ATOM 211 N LEU B 15 32.875 −42.141 −29.615 1.00 182.04 ATOM 212 CA LEU B 15 33.858 −43.231 −29.649 1.00 182.35 ATOM 213 C LEU B 15 34.176 −43.695 −31.065 1.00 189.26 ATOM 214 O LEU B 15 35.210 −44.338 −31.262 1.00 190.00 ATOM 215 CB LEU B 15 33.525 −44.417 −28.722 1.00 181.61 ATOM 216 CG LEU B 15 34.648 −44.729 −27.731 1.00 185.56 ATOM 217 CD1 LEU B 15 34.214 −44.482 −26.333 1.00 186.41 ATOM 218 CD2 LEU B 15 35.158 −46.129 −27.864 1.00 185.02 ATOM 219 N TYR B 16 33.327 −43.354 −32.063 1.00 186.36 ATOM 220 CA TYR B 16 33.721 −43.723 −33.404 1.00 186.42 ATOM 221 C TYR B 16 34.750 −42.737 −33.915 1.00 198.07 ATOM 222 O TYR B 16 35.846 −43.176 −34.299 1.00 199.72 ATOM 223 CB TYR B 16 32.591 −43.907 −34.397 1.00 184.87 ATOM 224 CG TYR B 16 33.123 −44.612 −35.621 1.00 184.81 ATOM 225 CD1 TYR B 16 34.233 −45.449 −35.541 1.00 186.73 ATOM 226 CD2 TYR B 16 32.516 −44.454 −36.856 1.00 186.19 ATOM 227 CE1 TYR B 16 34.729 −46.105 −36.664 1.00 189.25 ATOM 228 CE2 TYR B 16 32.994 −45.116 −37.988 1.00 188.21 ATOM 229 CZ TYR B 16 34.092 −45.955 −37.884 1.00 196.82 ATOM 230 OH TYR B 16 34.561 −46.634 −38.987 1.00 199.80 ATOM 231 N LEU B 17 34.443 −41.409 −33.875 1.00 197.09 ATOM 232 CA LEU B 17 35.423 −40.420 −34.328 1.00 197.79 ATOM 233 C LEU B 17 36.798 −40.640 −33.667 1.00 203.69 ATOM 234 O LEU B 17 37.797 −40.670 −34.385 1.00 204.11 ATOM 235 CB LEU B 17 34.941 −38.928 −34.362 1.00 197.83 ATOM 236 CG LEU B 17 34.071 −38.317 −33.224 1.00 201.49 ATOM 237 CD1 LEU B 17 34.365 −36.818 −33.034 1.00 201.24 ATOM 238 CD2 LEU B 17 32.601 −38.461 −33.524 1.00 203.23 ATOM 239 N VAL B 18 36.816 −40.985 −32.355 1.00 201.18 ATOM 240 CA VAL B 18 38.042 −41.235 −31.593 1.00 202.21 ATOM 241 C VAL B 18 38.853 −42.503 −31.985 1.00 211.88 ATOM 242 O VAL B 18 40.058 −42.516 −31.740 1.00 211.89 ATOM 243 CB VAL B 18 37.891 −41.009 −30.060 1.00 205.16 ATOM 244 CG1 VAL B 18 39.248 −40.846 −29.375 1.00 205.05 ATOM 245 CG2 VAL B 18 37.033 −39.787 −29.773 1.00 205.11 ATOM 246 N CYS B 19 38.246 −43.536 −32.625 1.00 212.92 ATOM 247 CA CYS B 19 39.047 −44.719 −33.007 1.00 215.52 ATOM 248 C CYS B 19 39.237 −44.835 −34.509 1.00 222.37 ATOM 249 O CYS B 19 40.242 −45.384 −34.944 1.00 222.72 ATOM 250 CB CYS B 19 38.510 −46.026 −32.412 1.00 216.15 ATOM 251 SG CYS B 19 37.878 −45.918 −30.719 1.00 219.65 ATOM 252 N GLY B 20 38.235 −44.436 −35.291 1.00 220.86 ATOM 253 CA GLY B 20 38.269 −44.572 −36.740 1.00 222.90 ATOM 254 C GLY B 20 38.616 −45.976 −37.198 1.00 231.14 ATOM 255 O GLY B 20 38.179 −46.977 −36.608 1.00 229.96 ATOM 256 N GLU B 21 39.565 −46.036 −38.113 1.00 232.64 ATOM 257 CA GLU B 21 40.038 −47.273 −38.722 1.00 235.94 ATOM 258 C GLU B 21 40.657 −48.280 −37.743 1.00 241.56 ATOM 259 O GLU B 21 40.635 −49.490 −38.011 1.00 243.26 ATOM 260 CB GLU B 21 40.980 −46.950 −39.900 1.00 240.01 ATOM 261 CG GLU B 21 40.285 −46.762 −41.255 1.00 255.11 ATOM 262 CD GLU B 21 40.965 −45.875 −42.288 1.00 284.51 ATOM 263 OE1 GLU B 21 42.182 −46.053 −42.522 1.00 289.71 ATOM 264 OE2 GLU B 21 40.263 −45.044 −42.912 1.00 276.74 ATOM 265 N ARG B 22 41.158 −47.804 −36.597 1.00 236.16 ATOM 266 CA ARG B 22 41.777 −48.670 −35.594 1.00 235.07 ATOM 267 C ARG B 22 40.776 −49.650 −34.986 1.00 236.02 ATOM 268 O ARG B 22 41.130 −50.761 −34.568 1.00 235.36 ATOM 269 CB ARG B 22 42.355 −47.790 −34.492 1.00 233.08 ATOM 270 CG ARG B 22 43.670 −47.117 −34.861 1.00 241.66 ATOM 271 CD ARG B 22 43.815 −46.031 −35.953 1.00 255.79 ATOM 272 NE ARG B 22 44.366 −46.527 −37.236 1.00 267.56 ATOM 273 CZ ARG B 22 45.529 −46.160 −37.788 1.00 278.48 ATOM 274 NH1 ARG B 22 46.345 −45.329 −37.151 1.00 266.51 ATOM 275 NH2 ARG B 22 45.895 −46.650 −38.967 1.00 258.49 ATOM 276 N GLY B 23 39.541 −49.195 −34.883 1.00 230.04 ATOM 277 CA GLY B 23 38.541 −50.026 −34.237 1.00 227.91 ATOM 278 C GLY B 23 38.646 −50.044 −32.710 1.00 228.27 ATOM 279 O GLY B 23 39.457 −49.333 −32.113 1.00 226.72 ATOM 280 N PHE B 24 37.778 −50.847 −32.037 1.00 223.26 ATOM 281 CA PHE B 24 37.610 −50.941 −30.560 1.00 221.71 ATOM 282 C PHE B 24 38.446 −52.073 −29.833 1.00 227.25 ATOM 283 O PHE B 24 39.307 −52.660 −30.494 1.00 228.96 ATOM 284 CB PHE B 24 36.095 −50.988 −30.223 1.00 221.97 ATOM 285 CG PHE B 24 35.264 −49.809 −30.714 1.00 222.42 ATOM 286 CD1 PHE B 24 34.611 −48.976 −29.818 1.00 224.25 ATOM 287 CD2 PHE B 24 35.105 −49.560 −32.073 1.00 224.10 ATOM 288 CE1 PHE B 24 33.841 −47.898 −30.273 1.00 224.62 ATOM 289 CE2 PHE B 24 34.366 −48.466 −32.520 1.00 226.18 ATOM 290 CZ PHE B 24 33.736 −47.644 −31.617 1.00 223.52 ATOM 291 O PHE B 25 37.255 −53.905 −26.185 1.00 218.98 ATOM 292 N PHE B 25 38.246 −52.347 −28.482 1.00 222.49 ATOM 293 CA PHE B 25 39.032 −53.388 −27.745 1.00 222.12 ATOM 294 C PHE B 25 38.325 −54.262 −26.694 1.00 221.10 ATOM 295 CB PHE B 25 40.442 −52.890 −27.287 1.00 225.15 ATOM 296 CG PHE B 25 40.864 −52.760 −25.823 1.00 226.85 ATOM 297 CD1 PHE B 25 41.962 −53.466 −25.333 1.00 230.25 ATOM 298 CD2 PHE B 25 40.275 −51.802 −24.988 1.00 228.79 ATOM 299 CE1 PHE B 25 42.425 −53.262 −24.020 1.00 231.09 ATOM 300 CE2 PHE B 25 40.729 −51.611 −23.666 1.00 231.35 ATOM 301 CZ PHE B 25 41.809 −52.331 −23.199 1.00 229.78 ATOM 302 O TYR B 26 39.488 −58.312 −24.237 1.00 198.04 ATOM 303 N TYR B 26 38.953 −55.436 −26.407 1.00 216.09 ATOM 304 CA TYR B 26 38.483 −56.481 −25.493 1.00 236.98 ATOM 305 C TYR B 26 39.559 −57.556 −25.218 1.00 245.61 ATOM 306 CB TYR B 26 37.176 −57.124 −26.024 1.00 238.00 ATOM 307 CG TYR B 26 37.184 −57.640 −27.456 1.00 240.71 ATOM 308 CD1 TYR B 26 36.631 −58.877 −27.774 1.00 242.87 ATOM 309 CD2 TYR B 26 37.674 −56.858 −28.505 1.00 242.05 ATOM 310 CE1 TYR B 26 36.596 −59.341 −29.090 1.00 244.60 ATOM 311 CE2 TYR B 26 37.663 −57.320 −29.822 1.00 243.99 ATOM 312 CZ TYR B 26 37.099 −58.554 −30.115 1.00 251.05 ATOM 313 OH TYR B 26 37.068 −59.015 −31.415 1.00 250.94 ATOM 315 N GLN C 1 11.311 −99.334 −34.481 1.00 197.85 ATOM 316 CA GLN C 1 11.076 −100.772 −34.608 1.00 197.44 ATOM 317 C GLN C 1 12.144 −101.453 −33.778 1.00 199.98 ATOM 318 O GLN C 1 12.893 −102.222 −34.362 1.00 201.18 ATOM 319 CB GLN C 1 11.244 −101.198 −36.098 1.00 201.73 ATOM 320 CG GLN C 1 10.262 −100.602 −37.118 1.00 209.58 ATOM 321 CD GLN C 1 10.377 −99.106 −37.366 1.00 224.21 ATOM 322 OE1 GLN C 1 11.470 −98.526 −37.428 1.00 219.38 ATOM 323 NE2 GLN C 1 9.237 −98.444 −37.528 1.00 214.07 ATOM 324 N VAL C 2 12.312 −101.099 −32.477 1.00 194.14 ATOM 325 CA VAL C 2 13.420 −101.605 −31.645 1.00 191.93 ATOM 326 C VAL C 2 13.431 −103.118 −31.472 1.00 201.23 ATOM 327 O VAL C 2 12.476 −103.682 −30.948 1.00 200.75 ATOM 328 CB VAL C 2 13.586 −100.870 −30.292 1.00 192.02 ATOM 329 CG1 VAL C 2 14.753 −101.437 −29.495 1.00 189.08 ATOM 330 CG2 VAL C 2 13.794 −99.380 −30.507 1.00 192.95 ATOM 331 N GLN C 3 14.526 −103.766 −31.907 1.00 202.34 ATOM 332 CA GLN C 3 14.717 −105.214 −31.806 1.00 203.12 ATOM 333 C GLN C 3 16.131 −105.584 −31.436 1.00 208.12 ATOM 334 O GLN C 3 17.096 −104.926 −31.837 1.00 207.84 ATOM 335 CB GLN C 3 14.356 −105.911 −33.113 1.00 207.35 ATOM 336 CG GLN C 3 12.872 −105.887 −33.415 1.00 218.60 ATOM 337 CD GLN C 3 12.507 −107.080 −34.229 1.00 242.36 ATOM 338 OE1 GLN C 3 12.817 −108.213 −33.851 1.00 238.61 ATOM 339 NE2 GLN C 3 11.849 −106.861 −35.360 1.00 237.02 ATOM 340 N LEU C 4 16.237 −106.648 −30.665 1.00 205.59 ATOM 341 CA LEU C 4 17.501 −107.205 −30.244 1.00 206.04 ATOM 342 C LEU C 4 17.300 −108.701 −30.296 1.00 216.94 ATOM 343 O LEU C 4 16.221 −109.194 −29.931 1.00 217.18 ATOM 344 CB LEU C 4 17.879 −106.781 −28.814 1.00 203.08 ATOM 345 CG LEU C 4 18.075 −105.295 −28.547 1.00 206.08 ATOM 346 CD1 LEU C 4 16.789 −104.684 −28.046 1.00 205.23 ATOM 347 CD2 LEU C 4 19.173 −105.066 −27.506 1.00 206.30 ATOM 348 N LYS C 5 18.304 −109.425 −30.825 1.00 218.00 ATOM 349 CA LYS C 5 18.255 −110.881 −30.949 1.00 219.97 ATOM 350 C LYS C 5 19.645 −111.452 −30.731 1.00 226.85 ATOM 351 O LYS C 5 20.617 −110.984 −31.316 1.00 227.49 ATOM 352 CB LYS C 5 17.705 −111.336 −32.322 1.00 225.47 ATOM 353 CG LYS C 5 16.634 −110.443 −32.965 1.00 243.07 ATOM 354 CD LYS C 5 16.061 −111.036 −34.239 1.00 255.86 ATOM 355 CE LYS C 5 15.154 −110.063 −34.958 1.00 261.22 ATOM 356 NZ LYS C 5 14.231 −110.755 −35.898 1.00 271.57 ATOM 357 N GLU C 6 19.730 −112.478 −29.909 1.00 225.50 ATOM 358 CA GLU C 6 20.977 −113.162 −29.590 1.00 226.93 ATOM 359 C GLU C 6 21.178 −114.369 −30.533 1.00 238.32 ATOM 360 O GLU C 6 20.208 −115.076 −30.857 1.00 240.02 ATOM 361 CB GLU C 6 20.945 −113.659 −28.134 1.00 226.31 ATOM 362 CG GLU C 6 20.497 −112.620 −27.114 1.00 231.37 ATOM 363 CD GLU C 6 18.994 −112.414 −26.960 1.00 243.21 ATOM 364 OE1 GLU C 6 18.238 −112.715 −27.913 1.00 223.73 ATOM 365 OE2 GLU C 6 18.578 −111.882 −25.908 1.00 237.51 ATOM 366 N SER C 7 22.429 −114.587 −30.981 1.00 238.35 ATOM 367 CA SER C 7 22.827 −115.745 −31.792 1.00 242.29 ATOM 368 C SER C 7 23.885 −116.420 −30.966 1.00 247.19 ATOM 369 O SER C 7 25.010 −115.916 −30.881 1.00 246.61 ATOM 370 CB SER C 7 23.382 −115.349 −33.164 1.00 248.70 ATOM 371 OG SER C 7 23.934 −114.042 −33.211 1.00 254.86 ATOM 372 N GLY C 8 23.489 −117.496 −30.296 1.00 244.80 ATOM 373 CA GLY C 8 24.366 −118.239 −29.410 1.00 244.75 ATOM 374 C GLY C 8 24.718 −119.591 −29.977 1.00 251.22 ATOM 375 O GLY C 8 24.148 −120.006 −30.995 1.00 252.95 ATOM 376 N PRO C 9 25.646 −120.311 −29.319 1.00 248.44 ATOM 377 CA PRO C 9 26.038 −121.625 −29.832 1.00 252.42 ATOM 378 C PRO C 9 25.159 −122.772 −29.330 1.00 256.51 ATOM 379 O PRO C 9 25.321 −123.906 −29.796 1.00 260.58 ATOM 380 CB PRO C 9 27.470 −121.756 −29.323 1.00 255.02 ATOM 381 CG PRO C 9 27.409 −121.113 −27.973 1.00 255.59 ATOM 382 CD PRO C 9 26.417 −119.969 −28.105 1.00 247.91 ATOM 383 N GLY C 10 24.278 −122.481 −28.367 1.00 248.27 ATOM 384 CA GLY C 10 23.399 −123.471 −27.761 1.00 248.79 ATOM 385 C GLY C 10 24.093 −124.338 −26.728 1.00 252.08 ATOM 386 O GLY C 10 23.618 −124.449 −25.593 1.00 250.75 ATOM 387 N LEU C 11 25.216 −124.971 −27.116 1.00 249.31 ATOM 388 CA LEU C 11 25.979 −125.865 −26.245 1.00 249.44 ATOM 389 C LEU C 11 27.421 −125.436 −26.109 1.00 252.08 ATOM 390 O LEU C 11 28.060 −125.034 −27.085 1.00 251.88 ATOM 391 CB LEU C 11 25.925 −127.316 −26.758 1.00 253.71 ATOM 392 CG LEU C 11 24.542 −127.948 −26.957 1.00 257.43 ATOM 393 CD1 LEU C 11 24.648 −129.329 −27.523 1.00 258.15 ATOM 394 CD2 LEU C 11 23.758 −127.978 −25.671 1.00 259.04 ATOM 395 N VAL C 12 27.930 −125.523 −24.892 1.00 248.11 ATOM 396 CA VAL C 12 29.316 −125.189 −24.589 1.00 248.35 ATOM 397 C VAL C 12 29.845 −126.333 −23.744 1.00 255.02 ATOM 398 O VAL C 12 29.216 −126.680 −22.746 1.00 254.64 ATOM 399 CB VAL C 12 29.476 −123.828 −23.845 1.00 248.71 ATOM 400 CG1 VAL C 12 30.923 −123.600 −23.391 1.00 249.58 ATOM 401 CG2 VAL C 12 29.011 −122.670 −24.713 1.00 246.11 ATOM 402 N ALA C 13 30.994 −126.915 −24.139 1.00 254.27 ATOM 403 CA ALA C 13 31.649 −127.980 −23.388 1.00 256.24 ATOM 404 C ALA C 13 32.343 −127.331 −22.195 1.00 258.29 ATOM 405 O ALA C 13 32.885 −126.225 −22.322 1.00 256.04 ATOM 406 CB ALA C 13 32.669 −128.691 −24.258 1.00 257.95 ATOM 407 N PRO C 14 32.333 −127.984 −21.020 1.00 255.63 ATOM 408 CA PRO C 14 32.994 −127.378 −19.855 1.00 254.38 ATOM 409 C PRO C 14 34.430 −127.007 −20.214 1.00 257.45 ATOM 410 O PRO C 14 35.072 −127.703 −21.003 1.00 257.51 ATOM 411 CB PRO C 14 32.896 −128.465 −18.787 1.00 256.74 ATOM 412 CG PRO C 14 31.773 −129.350 −19.240 1.00 260.04 ATOM 413 CD PRO C 14 31.809 −129.329 −20.716 1.00 256.97 ATOM 414 N SER C 15 34.886 −125.852 −19.713 1.00 253.09 ATOM 415 CA SER C 15 36.211 −125.274 −19.963 1.00 254.74 ATOM 416 C SER C 15 36.369 −124.537 −21.281 1.00 259.01 ATOM 417 O SER C 15 37.408 −123.912 −21.514 1.00 259.43 ATOM 418 CB SER C 15 37.326 −126.287 −19.753 1.00 258.90 ATOM 419 OG SER C 15 37.423 −126.568 −18.370 1.00 264.44 ATOM 420 N GLN C 16 35.340 −124.589 −22.138 1.00 255.08 ATOM 421 CA GLN C 16 35.339 −123.849 −23.397 1.00 254.27 ATOM 422 C GLN C 16 34.713 −122.446 −23.198 1.00 253.72 ATOM 423 O GLN C 16 34.105 −122.147 −22.161 1.00 249.79 ATOM 424 CB GLN C 16 34.598 −124.617 −24.506 1.00 256.25 ATOM 425 CG GLN C 16 35.484 −125.392 −25.469 1.00 258.15 ATOM 426 CD GLN C 16 36.796 −124.735 −25.838 1.00 266.06 ATOM 427 OE1 GLN C 16 37.874 −125.295 −25.615 1.00 263.70 ATOM 428 NE2 GLN C 16 36.736 −123.556 −26.447 1.00 251.39 ATOM 429 N SER C 17 34.847 −121.609 −24.220 1.00 250.17 ATOM 430 CA SER C 17 34.322 −120.262 −24.195 1.00 246.15 ATOM 431 C SER C 17 32.925 −120.187 −24.798 1.00 247.04 ATOM 432 O SER C 17 32.552 −121.019 −25.637 1.00 247.81 ATOM 433 CB SER C 17 35.248 −119.333 −24.968 1.00 251.44 ATOM 434 OG SER C 17 35.279 −119.725 −26.331 1.00 262.40 ATOM 435 N LEU C 18 32.179 −119.142 −24.390 1.00 239.71 ATOM 436 CA LEU C 18 30.845 −118.808 −24.877 1.00 236.03 ATOM 437 C LEU C 18 30.951 −117.535 −25.690 1.00 236.59 ATOM 438 O LEU C 18 31.449 −116.520 −25.201 1.00 234.42 ATOM 439 CB LEU C 18 29.866 −118.603 −23.711 1.00 232.94 ATOM 440 CG LEU C 18 28.521 −117.971 −24.018 1.00 234.99 ATOM 441 CD1 LEU C 18 27.694 −118.856 −24.950 1.00 236.30 ATOM 442 CD2 LEU C 18 27.746 −117.705 −22.724 1.00 235.75 ATOM 443 N SER C 19 30.497 −117.597 −26.927 1.00 233.64 ATOM 444 CA SER C 19 30.486 −116.438 −27.799 1.00 233.48 ATOM 445 C SER C 19 29.043 −116.213 −28.232 1.00 236.48 ATOM 446 O SER C 19 28.398 −117.163 −28.712 1.00 238.69 ATOM 447 CB SER C 19 31.385 −116.655 −29.015 1.00 240.18 ATOM 448 OG SER C 19 32.746 −116.388 −28.722 1.00 247.52 ATOM 449 N ILE C 20 28.515 −114.983 −28.020 1.00 227.96 ATOM 450 CA ILE C 20 27.159 −114.655 −28.446 1.00 224.65 ATOM 451 C ILE C 20 27.181 −113.355 −29.198 1.00 227.83 ATOM 452 O ILE C 20 27.792 −112.394 −28.741 1.00 226.77 ATOM 453 CB ILE C 20 26.121 −114.581 −27.298 1.00 223.52 ATOM 454 CG1 ILE C 20 26.103 −115.842 −26.457 1.00 222.52 ATOM 455 CG2 ILE C 20 24.722 −114.298 −27.873 1.00 224.78 ATOM 456 CD1 ILE C 20 25.387 −115.688 −25.173 1.00 212.68 ATOM 457 N THR C 21 26.484 −113.301 −30.325 1.00 225.00 ATOM 458 CA THR C 21 26.351 −112.052 −31.039 1.00 224.68 ATOM 459 C THR C 21 24.926 −111.537 −30.829 1.00 225.10 ATOM 460 O THR C 21 23.956 −112.268 −31.035 1.00 224.93 ATOM 461 CB THR C 21 26.677 −112.208 −32.522 1.00 232.85 ATOM 462 OG1 THR C 21 28.048 −112.566 −32.667 1.00 231.60 ATOM 463 CG2 THR C 21 26.395 −110.934 −33.306 1.00 230.66 ATOM 464 N CYS C 22 24.801 −110.280 −30.435 1.00 218.33 ATOM 465 CA CYS C 22 23.497 −109.651 −30.303 1.00 215.04 ATOM 466 C CYS C 22 23.364 −108.761 −31.526 1.00 220.75 ATOM 467 O CYS C 22 24.202 −107.870 −31.733 1.00 221.72 ATOM 468 CB CYS C 22 23.424 −108.838 −29.020 1.00 211.51 ATOM 469 SG CYS C 22 21.899 −107.871 −28.812 1.00 212.59 ATOM 470 N THR C 23 22.353 −109.025 −32.361 1.00 216.64 ATOM 471 CA THR C 23 22.121 −108.249 −33.574 1.00 217.30 ATOM 472 C THR C 23 20.965 −107.308 −33.226 1.00 216.14 ATOM 473 O THR C 23 19.918 −107.777 −32.766 1.00 212.99 ATOM 474 CB THR C 23 21.846 −109.183 −34.789 1.00 220.47 ATOM 475 OG1 THR C 23 21.795 −110.570 −34.404 1.00 211.66 ATOM 476 CG2 THR C 23 22.862 −109.019 −35.905 1.00 222.87 ATOM 477 N VAL C 24 21.171 −105.988 −33.359 1.00 211.41 ATOM 478 CA VAL C 24 20.105 −105.051 −33.006 1.00 208.14 ATOM 479 C VAL C 24 19.610 −104.298 −34.237 1.00 214.75 ATOM 480 O VAL C 24 20.346 −104.150 −35.218 1.00 217.17 ATOM 481 CB VAL C 24 20.502 −104.069 −31.874 1.00 208.29 ATOM 482 CG1 VAL C 24 21.138 −104.781 −30.695 1.00 205.19 ATOM 483 CG2 VAL C 24 21.425 −102.978 −32.394 1.00 210.37 ATOM 484 N SER C 25 18.377 −103.799 −34.176 1.00 211.21 ATOM 485 CA SER C 25 17.833 −102.978 −35.255 1.00 214.41 ATOM 486 C SER C 25 16.849 −101.965 −34.702 1.00 216.37 ATOM 487 O SER C 25 16.310 −102.161 −33.613 1.00 213.91 ATOM 488 CB SER C 25 17.206 −103.829 −36.362 1.00 221.50 ATOM 489 OG SER C 25 16.068 −104.545 −35.914 1.00 228.46 ATOM 490 N GLY C 26 16.640 −100.883 −35.441 1.00 213.67 ATOM 491 CA GLY C 26 15.697 −99.850 −35.046 1.00 211.94 ATOM 492 C GLY C 26 16.282 −98.735 −34.213 1.00 212.67 ATOM 493 O GLY C 26 15.547 −97.844 −33.789 1.00 212.53 ATOM 494 N PHE C 27 17.591 −98.769 −33.971 1.00 207.09 ATOM 495 CA PHE C 27 18.288 −97.732 −33.221 1.00 205.58 ATOM 496 C PHE C 27 19.756 −97.843 −33.493 1.00 209.71 ATOM 497 O PHE C 27 20.206 −98.942 −33.853 1.00 209.50 ATOM 498 CB PHE C 27 18.043 −97.875 −31.709 1.00 203.51 ATOM 499 CG PHE C 27 18.668 −99.083 −31.052 1.00 202.69 ATOM 500 CD2 PHE C 27 19.874 −98.974 −30.357 1.00 203.91 ATOM 501 CD1 PHE C 27 18.023 −100.322 −31.079 1.00 204.50 ATOM 502 CE2 PHE C 27 20.441 −100.088 −29.726 1.00 204.86 ATOM 503 CE1 PHE C 27 18.578 −101.438 −30.434 1.00 203.53 ATOM 504 CZ PHE C 27 19.782 −101.312 −29.755 1.00 201.77 ATOM 505 N PRO C 28 20.523 −96.747 −33.243 1.00 206.63 ATOM 506 CA PRO C 28 21.977 −96.799 −33.460 1.00 208.79 ATOM 507 C PRO C 28 22.748 −97.154 −32.183 1.00 210.19 ATOM 508 O PRO C 28 22.468 −96.590 −31.128 1.00 208.24 ATOM 509 CB PRO C 28 22.310 −95.377 −33.942 1.00 214.37 ATOM 510 CG PRO C 28 20.991 −94.554 −33.784 1.00 217.56 ATOM 511 CD PRO C 28 20.103 −95.373 −32.904 1.00 208.35 ATOM 512 N LEU C 29 23.718 −98.091 −32.272 1.00 206.64 ATOM 513 CA LEU C 29 24.543 −98.499 −31.123 1.00 203.72 ATOM 514 C LEU C 29 25.421 −97.342 −30.648 1.00 207.57 ATOM 515 O LEU C 29 25.982 −97.406 −29.552 1.00 206.13 ATOM 516 CB LEU C 29 25.417 −99.729 −31.460 1.00 204.57 ATOM 517 CG LEU C 29 24.711 −101.088 −31.565 1.00 206.92 ATOM 518 CD1 LEU C 29 25.657 −102.149 −32.081 1.00 209.72 ATOM 519 CD2 LEU C 29 24.138 −101.519 −30.229 1.00 204.33 ATOM 520 N THR C 30 25.547 −96.288 −31.469 1.00 205.88 ATOM 521 CA THR C 30 26.348 −95.132 −31.087 1.00 207.97 ATOM 522 C THR C 30 25.623 −94.319 −29.982 1.00 210.17 ATOM 523 O THR C 30 26.282 −93.666 −29.177 1.00 210.78 ATOM 524 CB THR C 30 26.718 −94.262 −32.324 1.00 216.82 ATOM 525 OG1 THR C 30 25.548 −93.677 −32.878 1.00 213.22 ATOM 526 CG2 THR C 30 27.421 −95.039 −33.418 1.00 218.01 ATOM 527 N ALA C 31 24.272 −94.367 −29.945 1.00 203.75 ATOM 528 CA ALA C 31 23.427 −93.580 −29.026 1.00 200.55 ATOM 529 C ALA C 31 22.799 −94.337 −27.872 1.00 196.90 ATOM 530 O ALA C 31 22.058 −93.747 −27.101 1.00 193.76 ATOM 531 CB ALA C 31 22.329 −92.882 −29.823 1.00 202.43 ATOM 532 N TYR C 32 23.008 −95.637 −27.795 1.00 191.80 ATOM 533 CA TYR C 32 22.377 −96.430 −26.752 1.00 188.57 ATOM 534 C TYR C 32 23.357 −97.434 −26.205 1.00 193.25 ATOM 535 O TYR C 32 24.368 −97.757 −26.841 1.00 195.66 ATOM 536 CB TYR C 32 21.118 −97.154 −27.290 1.00 188.15 ATOM 537 CG TYR C 32 19.949 −96.239 −27.595 1.00 190.21 ATOM 538 CD1 TYR C 32 19.816 −95.632 −28.841 1.00 194.62 ATOM 539 CD2 TYR C 32 18.979 −95.978 −26.642 1.00 189.28 ATOM 540 CE1 TYR C 32 18.762 −94.763 −29.117 1.00 195.12 ATOM 541 CE2 TYR C 32 17.915 −95.117 −26.910 1.00 190.93 ATOM 542 CZ TYR C 32 17.802 −94.522 −28.155 1.00 197.11 ATOM 543 OH TYR C 32 16.735 −93.700 −28.434 1.00 194.23 ATOM 544 N GLY C 33 23.081 −97.913 −25.016 1.00 187.51 ATOM 545 CA GLY C 33 23.960 −98.920 −24.454 1.00 186.96 ATOM 546 C GLY C 33 23.301 −100.254 −24.667 1.00 188.61 ATOM 547 O GLY C 33 22.103 −100.298 −24.990 1.00 187.43 ATOM 548 N VAL C 34 24.074 −101.339 −24.518 1.00 184.25 ATOM 549 CA VAL C 34 23.529 −102.694 −24.602 1.00 182.32 ATOM 550 C VAL C 34 24.083 −103.493 −23.444 1.00 184.30 ATOM 551 O VAL C 34 25.299 −103.567 −23.252 1.00 183.93 ATOM 552 CB VAL C 34 23.753 −103.416 −25.960 1.00 187.86 ATOM 553 CG1 VAL C 34 23.394 −104.906 −25.865 1.00 186.65 ATOM 554 CG2 VAL C 34 22.948 −102.748 −27.071 1.00 188.75 ATOM 555 N ASN C 35 23.189 −104.086 −22.678 1.00 180.82 ATOM 556 CA ASN C 35 23.557 −104.903 −21.534 1.00 182.01 ATOM 557 C ASN C 35 23.344 −106.389 −21.799 1.00 188.69 ATOM 558 O ASN C 35 22.603 −106.757 −22.715 1.00 190.26 ATOM 559 CB ASN C 35 22.700 −104.531 −20.339 1.00 183.40 ATOM 560 CG ASN C 35 22.572 −103.068 −20.112 1.00 215.20 ATOM 561 OD1 ASN C 35 22.234 −102.303 −21.019 1.00 216.32 ATOM 562 ND2 ASN C 35 22.797 −102.650 −18.897 1.00 209.15 ATOM 563 N TRP C 36 23.949 −107.240 −20.952 1.00 183.77 ATOM 564 CA TRP C 36 23.749 −108.664 −21.002 1.00 182.96 ATOM 565 C TRP C 36 23.333 −109.071 −19.659 1.00 181.87 ATOM 566 O TRP C 36 23.905 −108.642 −18.658 1.00 180.07 ATOM 567 CB TRP C 36 25.007 −109.385 −21.393 1.00 184.61 ATOM 568 CG TRP C 36 25.387 −109.152 −22.803 1.00 188.10 ATOM 569 CD1 TRP C 36 26.153 −108.131 −23.296 1.00 192.31 ATOM 570 CD2 TRP C 36 25.012 −109.962 −23.924 1.00 189.30 ATOM 571 NE1 TRP C 36 26.290 −108.261 −24.660 1.00 193.92 ATOM 572 CE2 TRP C 36 25.599 −109.380 −25.072 1.00 195.52 ATOM 573 CE3 TRP C 36 24.249 −111.146 −24.068 1.00 190.76 ATOM 574 CZ2 TRP C 36 25.444 −109.938 −26.347 1.00 196.26 ATOM 575 CZ3 TRP C 36 24.093 −111.692 −25.331 1.00 193.58 ATOM 576 CH2 TRP C 36 24.682 −111.091 −26.453 1.00 195.59 ATOM 577 N VAL C 37 22.304 −109.875 −19.636 1.00 179.40 ATOM 578 CA VAL C 37 21.676 −110.412 −18.444 1.00 181.70 ATOM 579 C VAL C 37 21.515 −111.952 −18.656 1.00 195.83 ATOM 580 O VAL C 37 21.262 −112.399 −19.778 1.00 197.57 ATOM 581 CB VAL C 37 20.305 −109.685 −18.247 1.00 182.78 ATOM 582 CG1 VAL C 37 19.437 −110.335 −17.172 1.00 182.86 ATOM 583 CG2 VAL C 37 20.519 −108.215 −17.935 1.00 181.91 ATOM 584 N ARG C 38 21.672 −112.761 −17.602 1.00 195.92 ATOM 585 CA ARG C 38 21.411 −114.193 −17.730 1.00 196.88 ATOM 586 C ARG C 38 20.446 −114.670 −16.654 1.00 204.40 ATOM 587 O ARG C 38 20.318 −114.045 −15.582 1.00 205.00 ATOM 588 CB ARG C 38 22.686 −115.025 −17.768 1.00 194.92 ATOM 589 CG ARG C 38 23.368 −115.188 −16.421 1.00 201.46 ATOM 590 CD ARG C 38 24.634 −115.980 −16.563 1.00 208.80 ATOM 591 NE ARG C 38 25.328 −116.107 −15.287 1.00 215.75 ATOM 592 CZ ARG C 38 26.477 −116.753 −15.116 1.00 235.95 ATOM 593 NH1 ARG C 38 27.082 −117.335 −16.146 1.00 233.11 ATOM 594 NH2 ARG C 38 27.025 −116.835 −13.912 1.00 222.08 ATOM 595 N GLN C 39 19.749 −115.758 −16.959 1.00 203.58 ATOM 596 CA GLN C 39 18.802 −116.343 −16.031 1.00 207.41 ATOM 597 C GLN C 39 18.976 −117.875 −15.962 1.00 216.73 ATOM 598 O GLN C 39 18.597 −118.578 −16.911 1.00 217.45 ATOM 599 CB GLN C 39 17.369 −115.958 −16.412 1.00 208.85 ATOM 600 CG GLN C 39 16.281 −116.423 −15.442 1.00 230.23 ATOM 601 CD GLN C 39 14.944 −115.800 −15.781 1.00 251.88 ATOM 602 OE1 GLN C 39 14.645 −115.543 −16.955 1.00 254.54 ATOM 603 NE2 GLN C 39 14.103 −115.540 −14.769 1.00 232.99 ATOM 604 N PRO C 40 19.552 −118.424 −14.862 1.00 215.34 ATOM 605 CA PRO C 40 19.636 −119.880 −14.754 1.00 217.60 ATOM 606 C PRO C 40 18.204 −120.420 −14.689 1.00 221.18 ATOM 607 O PRO C 40 17.294 −119.737 −14.188 1.00 219.80 ATOM 608 CB PRO C 40 20.383 −120.087 −13.435 1.00 221.76 ATOM 609 CG PRO C 40 21.125 −118.785 −13.218 1.00 223.58 ATOM 610 CD PRO C 40 20.115 −117.781 −13.657 1.00 217.27 ATOM 611 N PRO C 41 17.966 −121.622 −15.241 1.00 219.64 ATOM 612 CA PRO C 41 16.595 −122.164 −15.232 1.00 222.58 ATOM 613 C PRO C 41 15.928 −122.098 −13.860 1.00 227.93 ATOM 614 O PRO C 41 16.542 −122.448 −12.856 1.00 228.37 ATOM 615 CB PRO C 41 16.768 −123.584 −15.777 1.00 227.48 ATOM 616 CG PRO C 41 18.057 −123.518 −16.601 1.00 228.79 ATOM 617 CD PRO C 41 18.930 −122.565 −15.856 1.00 221.71 ATOM 618 N GLY C 42 14.728 −121.528 −13.827 1.00 225.44 ATOM 619 CA GLY C 42 13.954 −121.351 −12.605 1.00 229.26 ATOM 620 C GLY C 42 14.552 −120.401 −11.588 1.00 232.21 ATOM 621 O GLY C 42 14.102 −120.363 −10.443 1.00 234.41 ATOM 622 N LYS C 43 15.565 −119.630 −11.977 1.00 226.56 ATOM 623 CA LYS C 43 16.175 −118.671 −11.054 1.00 226.60 ATOM 624 C LYS C 43 15.999 −117.244 −11.529 1.00 230.10 ATOM 625 O LYS C 43 15.356 −117.016 −12.553 1.00 228.89 ATOM 626 CB LYS C 43 17.646 −119.011 −10.774 1.00 227.73 ATOM 627 CG LYS C 43 17.801 −120.286 −9.928 1.00 235.99 ATOM 628 CD LYS C 43 19.257 −120.582 −9.548 1.00 229.20 ATOM 629 CE LYS C 43 19.408 −121.717 −8.566 1.00 223.07 ATOM 630 NZ LYS C 43 19.240 −121.255 −7.164 1.00 226.42 ATOM 631 N GLY C 44 16.528 −116.298 −10.766 1.00 227.49 ATOM 632 CA GLY C 44 16.403 −114.882 −11.077 1.00 224.80 ATOM 633 C GLY C 44 17.303 −114.358 −12.177 1.00 224.29 ATOM 634 O GLY C 44 17.899 −115.127 −12.948 1.00 222.39 ATOM 635 N LEU C 45 17.417 −113.015 −12.219 1.00 218.10 ATOM 636 CA LEU C 45 18.219 −112.305 −13.207 1.00 212.98 ATOM 637 C LEU C 45 19.522 −111.854 −12.644 1.00 212.75 ATOM 638 O LEU C 45 19.599 −111.383 −11.505 1.00 213.02 ATOM 639 CB LEU C 45 17.451 −111.107 −13.773 1.00 211.35 ATOM 640 CG LEU C 45 16.101 −111.428 −14.388 1.00 216.60 ATOM 641 CD1 LEU C 45 15.349 −110.177 −14.707 1.00 214.41 ATOM 642 CD2 LEU C 45 16.262 −112.308 −15.635 1.00 220.84 ATOM 643 N GLU C 46 20.550 −111.996 −13.449 1.00 206.80 ATOM 644 CA GLU C 46 21.878 −111.598 −13.047 1.00 207.29 ATOM 645 C GLU C 46 22.413 −110.658 −14.091 1.00 207.36 ATOM 646 O GLU C 46 22.516 −111.028 −15.255 1.00 204.84 ATOM 647 CB GLU C 46 22.804 −112.832 −12.892 1.00 210.88 ATOM 648 CG GLU C 46 24.185 −112.521 −12.308 1.00 226.10 ATOM 649 CD GLU C 46 25.215 −113.640 −12.282 1.00 249.52 ATOM 650 OE1 GLU C 46 26.176 −113.524 −11.488 1.00 234.02 ATOM 651 OE2 GLU C 46 25.080 −114.613 −13.061 1.00 250.50 ATOM 652 N TRP C 47 22.777 −109.450 −13.683 1.00 204.03 ATOM 653 CA TRP C 47 23.334 −108.509 −14.630 1.00 202.23 ATOM 654 C TRP C 47 24.787 −108.837 −14.858 1.00 203.49 ATOM 655 O TRP C 47 25.547 −108.937 −13.899 1.00 205.62 ATOM 656 CB TRP C 47 23.173 −107.095 −14.114 1.00 202.22 ATOM 657 CG TRP C 47 23.687 −106.056 −15.067 1.00 202.39 ATOM 658 CD1 TRP C 47 23.016 −105.492 −16.116 1.00 203.89 ATOM 659 CD2 TRP C 47 24.973 −105.422 −15.020 1.00 202.70 ATOM 660 NE1 TRP C 47 23.803 −104.541 −16.724 1.00 202.88 ATOM 661 CE2 TRP C 47 25.000 −104.459 −16.054 1.00 205.42 ATOM 662 CE3 TRP C 47 26.088 −105.536 −14.164 1.00 205.20 ATOM 663 CZ2 TRP C 47 26.096 −103.621 −16.259 1.00 205.20 ATOM 664 CZ3 TRP C 47 27.152 −104.679 −14.348 1.00 207.04 ATOM 665 CH2 TRP C 47 27.158 −103.748 −15.396 1.00 206.69 ATOM 666 N LEU C 48 25.177 −108.976 −16.117 1.00 196.92 ATOM 667 CA LEU C 48 26.543 −109.356 −16.455 1.00 197.76 ATOM 668 C LEU C 48 27.500 −108.205 −16.784 1.00 202.09 ATOM 669 O LEU C 48 28.650 −108.204 −16.346 1.00 203.51 ATOM 670 CB LEU C 48 26.540 −110.406 −17.583 1.00 197.52 ATOM 671 CG LEU C 48 25.688 −111.687 −17.397 1.00 201.93 ATOM 672 CD1 LEU C 48 25.764 −112.574 −18.635 1.00 201.41 ATOM 673 CD2 LEU C 48 26.122 −112.477 −16.164 1.00 206.21 ATOM 674 N GLY C 49 27.034 −107.257 −17.572 1.00 197.73 ATOM 675 CA GLY C 49 27.842 −106.124 −17.996 1.00 199.02 ATOM 676 C GLY C 49 27.114 −105.325 −19.056 1.00 203.53 ATOM 677 O GLY C 49 26.000 −105.698 −19.443 1.00 203.14 ATOM 678 N MET C 50 27.702 −104.206 −19.511 1.00 199.85 ATOM 679 CA MET C 50 27.123 −103.389 −20.585 1.00 197.85 ATOM 680 C MET C 50 28.200 −102.658 −21.372 1.00 200.95 ATOM 681 O MET C 50 29.350 −102.539 −20.919 1.00 200.81 ATOM 682 CB MET C 50 25.994 −102.439 −20.105 1.00 199.09 ATOM 683 CG MET C 50 26.420 −101.306 −19.146 1.00 204.41 ATOM 684 SD MET C 50 25.420 −99.723 −19.238 1.00 208.15 ATOM 685 CE MET C 50 25.943 −99.102 −20.833 1.00 205.84 ATOM 686 N ILE C 51 27.831 −102.217 −22.569 1.00 197.98 ATOM 687 CA ILE C 51 28.701 −101.428 −23.416 1.00 201.37 ATOM 688 C ILE C 51 27.969 −100.113 −23.758 1.00 208.60 ATOM 689 O ILE C 51 26.844 −100.119 −24.290 1.00 205.82 ATOM 690 CB ILE C 51 29.224 −102.187 −24.660 1.00 205.50 ATOM 691 CG1 ILE C 51 30.319 −101.341 −25.375 1.00 209.38 ATOM 692 CG2 ILE C 51 28.061 −102.569 −25.603 1.00 204.42 ATOM 693 CD1 ILE C 51 31.298 −102.123 −26.288 1.00 214.02 ATOM 694 N TRP C 52 28.614 −98.993 −23.402 1.00 210.00 ATOM 695 CA TRP C 52 28.094 −97.647 −23.620 1.00 211.69 ATOM 696 C TRP C 52 28.235 −97.257 −25.070 1.00 219.19 ATOM 697 O TRP C 52 29.000 −97.874 −25.813 1.00 219.81 ATOM 698 CB TRP C 52 28.856 −96.628 −22.757 1.00 213.35 ATOM 699 CG TRP C 52 28.680 −96.786 −21.271 1.00 212.95 ATOM 700 CD1 TRP C 52 29.347 −97.653 −20.466 1.00 215.60 ATOM 701 CD2 TRP C 52 27.831 −96.008 −20.404 1.00 212.40 ATOM 702 NE1 TRP C 52 28.966 −97.475 −19.157 1.00 214.41 ATOM 703 CE2 TRP C 52 28.026 −96.482 −19.091 1.00 215.77 ATOM 704 CE3 TRP C 52 26.943 −94.940 −20.605 1.00 214.25 ATOM 705 CZ2 TRP C 52 27.355 −95.937 −17.984 1.00 215.34 ATOM 706 CZ3 TRP C 52 26.259 −94.418 −19.510 1.00 215.51 ATOM 707 CH2 TRP C 52 26.464 −94.918 −18.220 1.00 215.83 ATOM 708 N GLY C 53 27.542 −96.196 −25.451 1.00 218.79 ATOM 709 CA GLY C 53 27.620 −95.683 −26.810 1.00 222.72 ATOM 710 C GLY C 53 29.044 −95.475 −27.285 1.00 232.92 ATOM 711 O GLY C 53 29.365 −95.826 −28.423 1.00 236.09 ATOM 712 N ASP C 54 29.923 −94.958 −26.399 1.00 230.73 ATOM 713 CA ASP C 54 31.328 −94.674 −26.720 1.00 235.34 ATOM 714 C ASP C 54 32.263 −95.903 −26.742 1.00 235.81 ATOM 715 O ASP C 54 33.466 −95.752 −26.975 1.00 239.34 ATOM 716 CB ASP C 54 31.882 −93.583 −25.777 1.00 240.48 ATOM 717 CG ASP C 54 32.190 −94.043 −24.355 1.00 253.43 ATOM 718 OD1 ASP C 54 31.789 −95.167 −23.989 1.00 251.99 ATOM 719 OD2 ASP C 54 32.815 −93.268 −23.603 1.00 260.96 ATOM 720 N GLY C 55 31.717 −97.082 −26.456 1.00 225.76 ATOM 721 CA GLY C 55 32.500 −98.308 −26.440 1.00 224.79 ATOM 722 C GLY C 55 33.111 −98.656 −25.104 1.00 224.61 ATOM 723 O GLY C 55 33.688 −99.736 −24.966 1.00 223.85 ATOM 724 N ASN C 56 33.002 −97.762 −24.112 1.00 219.23 ATOM 725 CA ASN C 56 33.515 −98.055 −22.780 1.00 218.32 ATOM 726 C ASN C 56 32.591 −99.101 −22.181 1.00 217.60 ATOM 727 O ASN C 56 31.432 −99.204 −22.593 1.00 213.43 ATOM 728 CB ASN C 56 33.725 −96.759 −21.939 1.00 220.27 ATOM 729 CG ASN C 56 32.974 −96.501 −20.638 1.00 235.55 ATOM 730 OD1 ASN C 56 32.899 −97.346 −19.743 1.00 228.70 ATOM 731 ND2 ASN C 56 32.595 −95.235 −20.419 1.00 224.99 ATOM 732 N THR C 57 33.123 −99.944 −21.297 1.00 215.56 ATOM 733 CA THR C 57 32.343 −101.036 −20.711 1.00 212.34 ATOM 734 C THR C 57 32.343 −101.064 −19.207 1.00 217.65 ATOM 735 O THR C 57 33.237 −100.515 −18.550 1.00 220.14 ATOM 736 CB THR C 57 32.892 −102.378 −21.151 1.00 221.76 ATOM 737 OG1 THR C 57 34.263 −102.456 −20.765 1.00 223.39 ATOM 738 CG2 THR C 57 32.766 −102.581 −22.624 1.00 224.51 ATOM 739 N ASP C 58 31.343 −101.764 −18.673 1.00 212.49 ATOM 740 CA ASP C 58 31.196 −102.017 −17.255 1.00 212.70 ATOM 741 C ASP C 58 30.925 −103.506 −17.113 1.00 217.17 ATOM 742 O ASP C 58 30.044 −104.026 −17.807 1.00 215.62 ATOM 743 CB ASP C 58 30.042 −101.197 −16.655 1.00 212.25 ATOM 744 CG ASP C 58 30.359 −99.743 −16.431 1.00 216.30 ATOM 745 OD1 ASP C 58 31.446 −99.441 −15.868 1.00 218.24 ATOM 746 OD2 ASP C 58 29.524 −98.908 −16.792 1.00 220.08 ATOM 747 N TYR C 59 31.697 −104.197 −16.248 1.00 214.67 ATOM 748 CA TYR C 59 31.510 −105.620 −16.014 1.00 213.53 ATOM 749 C TYR C 59 31.189 −105.896 −14.578 1.00 218.58 ATOM 750 O TYR C 59 31.684 −105.193 −13.689 1.00 218.59 ATOM 751 CB TYR C 59 32.752 −106.409 −16.402 1.00 217.31 ATOM 752 CG TYR C 59 33.173 −106.250 −17.844 1.00 220.65 ATOM 753 CD1 TYR C 59 32.277 −106.487 −18.884 1.00 220.40 ATOM 754 CD2 TYR C 59 34.479 −105.900 −18.173 1.00 225.31 ATOM 755 CE1 TYR C 59 32.665 −106.352 −20.211 1.00 222.17 ATOM 756 CE2 TYR C 59 34.879 −105.763 −19.497 1.00 227.62 ATOM 757 CZ TYR C 59 33.969 −105.988 −20.511 1.00 232.58 ATOM 758 OH TYR C 59 34.380 −105.861 −21.812 1.00 235.10 ATOM 759 N ASN C 60 30.362 −106.936 −14.352 1.00 217.23 ATOM 760 CA ASN C 60 29.962 −107.381 −13.021 1.00 219.89 ATOM 761 C ASN C 60 31.230 −107.895 −12.352 1.00 230.39 ATOM 762 O ASN C 60 31.969 −108.669 −12.973 1.00 231.39 ATOM 763 CB ASN C 60 28.874 −108.477 −13.116 1.00 219.44 ATOM 764 CG ASN C 60 28.359 −109.021 −11.790 1.00 245.88 ATOM 765 OD1 ASN C 60 29.104 −109.483 −10.924 1.00 237.16 ATOM 766 ND2 ASN C 60 27.045 −109.050 −11.625 1.00 240.38 ATOM 767 N SER C 61 31.526 −107.416 −11.125 1.00 230.14 ATOM 768 CA SER C 61 32.720 −107.822 −10.369 1.00 233.35 ATOM 769 C SER C 61 32.950 −109.348 −10.296 1.00 236.26 ATOM 770 O SER C 61 34.106 −109.786 −10.235 1.00 237.09 ATOM 771 CB SER C 61 32.704 −107.212 −8.976 1.00 240.05 ATOM 772 OG SER C 61 31.447 −107.405 −8.347 1.00 247.18 ATOM 773 N ALA C 62 31.866 −110.153 −10.369 1.00 230.99 ATOM 774 CA ALA C 62 32.001 −111.607 −10.372 1.00 231.64 ATOM 775 C ALA C 62 32.853 −112.072 −11.589 1.00 234.58 ATOM 776 O ALA C 62 33.483 −113.130 −11.530 1.00 236.98 ATOM 777 CB ALA C 62 30.626 −112.269 −10.381 1.00 230.76 ATOM 778 N LEU C 63 32.895 −111.240 −12.657 1.00 227.35 ATOM 779 CA LEU C 63 33.614 −111.470 −13.894 1.00 226.19 ATOM 780 C LEU C 63 34.951 −110.859 −13.923 1.00 234.56 ATOM 781 O LEU C 63 35.209 −109.744 −14.419 1.00 230.13 ATOM 782 CB LEU C 63 32.811 −111.226 −15.154 1.00 222.49 ATOM 783 CG LEU C 63 31.887 −112.376 −15.491 1.00 224.54 ATOM 784 CD1 LEU C 63 30.527 −111.904 −15.975 1.00 221.75 ATOM 785 CD2 LEU C 63 32.505 −113.267 −16.484 1.00 226.67 ATOM 786 N LYS C 64 35.764 −111.610 −13.210 1.00 240.77 ATOM 787 CA LYS C 64 37.188 −111.574 −12.992 1.00 247.57 ATOM 788 C LYS C 64 37.876 −111.925 −14.315 1.00 258.44 ATOM 789 O LYS C 64 38.385 −113.049 −14.490 1.00 260.48 ATOM 790 CB LYS C 64 37.560 −112.651 −11.952 1.00 252.35 ATOM 791 CG LYS C 64 37.101 −112.398 −10.523 1.00 256.92 ATOM 792 CD LYS C 64 37.818 −113.370 −9.577 1.00 257.87 ATOM 793 CE LYS C 64 37.526 −113.121 −8.117 1.00 256.02 ATOM 794 NZ LYS C 64 38.024 −114.232 −7.262 1.00 257.37 ATOM 795 N SER C 65 37.849 −110.970 −15.261 1.00 256.63 ATOM 796 CA SER C 65 38.473 −111.100 −16.576 1.00 258.13 ATOM 797 C SER C 65 37.924 −112.257 −17.440 1.00 260.27 ATOM 798 O SER C 65 38.493 −112.505 −18.504 1.00 261.93 ATOM 799 CB SER C 65 39.999 −111.158 −16.455 1.00 266.26 ATOM 800 OG SER C 65 40.525 −110.095 −15.674 1.00 270.82 ATOM 801 N ARG C 66 36.819 −112.944 −17.030 1.00 252.90 ATOM 802 CA ARG C 66 36.253 −113.996 −17.888 1.00 250.89 ATOM 803 C ARG C 66 35.377 −113.347 −18.961 1.00 253.03 ATOM 804 O ARG C 66 35.226 −113.954 −20.012 1.00 253.97 ATOM 805 CB ARG C 66 35.370 −115.035 −17.165 1.00 246.36 ATOM 806 CG ARG C 66 35.776 −115.462 −15.774 1.00 249.47 ATOM 807 CD ARG C 66 34.612 −116.134 −15.048 1.00 247.68 ATOM 808 NE ARG C 66 34.204 −117.382 −15.698 1.00 241.84 ATOM 809 CZ ARG C 66 33.252 −118.201 −15.262 1.00 246.01 ATOM 810 NH1 ARG C 66 32.602 −117.937 −14.132 1.00 218.66 ATOM 811 NH2 ARG C 66 32.977 −119.316 −15.924 1.00 238.07 ATOM 812 N LEU C 67 34.801 −112.135 −18.705 1.00 246.00 ATOM 813 CA LEU C 67 33.894 −111.466 −19.640 1.00 242.37 ATOM 814 C LEU C 67 34.443 −110.317 −20.489 1.00 243.25 ATOM 815 O LEU C 67 35.098 −109.406 −19.983 1.00 244.65 ATOM 816 CB LEU C 67 32.608 −111.032 −18.934 1.00 239.67 ATOM 817 CG LEU C 67 31.512 −110.331 −19.771 1.00 243.36 ATOM 818 CD1 LEU C 67 30.780 −111.318 −20.678 1.00 243.13 ATOM 819 CD2 LEU C 67 30.483 −109.641 −18.881 1.00 245.65 ATOM 820 N SER C 68 34.090 −110.351 −21.785 1.00 235.74 ATOM 821 CA SER C 68 34.421 −109.333 −22.771 1.00 235.00 ATOM 822 C SER C 68 33.167 −108.918 −23.554 1.00 232.82 ATOM 823 O SER C 68 32.447 −109.781 −24.064 1.00 231.52 ATOM 824 CB SER C 68 35.488 −109.847 −23.733 1.00 240.32 ATOM 825 OG SER C 68 36.788 −109.660 −23.195 1.00 247.20 ATOM 826 N ILE C 69 32.892 −107.603 −23.626 1.00 224.77 ATOM 827 CA ILE C 69 31.802 −107.063 −24.436 1.00 220.28 ATOM 828 C ILE C 69 32.430 −106.073 −25.423 1.00 224.29 ATOM 829 O ILE C 69 33.070 −105.111 −25.004 1.00 224.82 ATOM 830 CB ILE C 69 30.642 −106.410 −23.641 1.00 218.88 ATOM 831 CG1 ILE C 69 30.090 −107.332 −22.561 1.00 215.03 ATOM 832 CG2 ILE C 69 29.515 −105.971 −24.602 1.00 219.69 ATOM 833 CD1 ILE C 69 29.211 −106.613 −21.602 1.00 209.36 ATOM 834 N SER C 70 32.275 −106.323 −26.719 1.00 220.60 ATOM 835 CA SER C 70 32.773 −105.437 −27.767 1.00 223.29 ATOM 836 C SER C 70 31.634 −105.243 −28.746 1.00 225.11 ATOM 837 O SER C 70 30.589 −105.876 −28.600 1.00 220.78 ATOM 838 CB SER C 70 33.996 −106.037 −28.461 1.00 231.14 ATOM 839 OG SER C 70 33.843 −107.420 −28.748 1.00 237.65 ATOM 840 N LYS C 71 31.805 −104.375 −29.731 1.00 225.14 ATOM 841 CA LYS C 71 30.732 −104.160 −30.685 1.00 224.70 ATOM 842 C LYS C 71 31.254 −103.643 −31.996 1.00 233.46 ATOM 843 O LYS C 71 32.394 −103.167 −32.084 1.00 236.49 ATOM 844 CB LYS C 71 29.711 −103.156 −30.116 1.00 224.58 ATOM 845 CG LYS C 71 30.291 −101.743 −29.877 1.00 239.01 ATOM 846 CD LYS C 71 29.235 −100.743 −29.366 1.00 235.71 ATOM 847 CE LYS C 71 29.757 −99.331 −29.167 1.00 233.04 ATOM 848 NZ LYS C 71 28.647 −98.347 −29.114 1.00 235.49 ATOM 849 N ASP C 72 30.387 −103.687 −33.000 1.00 231.02 ATOM 850 CA ASP C 72 30.674 −103.135 −34.301 1.00 236.86 ATOM 851 C ASP C 72 29.493 −102.251 −34.621 1.00 240.52 ATOM 852 O ASP C 72 28.433 −102.755 −35.014 1.00 238.21 ATOM 853 CB ASP C 72 30.849 −104.234 −35.363 1.00 242.01 ATOM 854 CG ASP C 72 31.255 −103.698 −36.739 1.00 256.61 ATOM 855 OD1 ASP C 72 30.760 −102.610 −37.136 1.00 258.39 ATOM 856 OD2 ASP C 72 32.062 −104.358 −37.415 1.00 263.41 ATOM 857 N ASN C 73 29.668 −100.936 −34.457 1.00 239.20 ATOM 858 CA ASN C 73 28.585 −100.001 −34.712 1.00 238.45 ATOM 859 C ASN C 73 27.989 −100.111 −36.105 1.00 245.64 ATOM 860 O ASN C 73 26.765 −100.127 −36.238 1.00 243.29 ATOM 861 CB ASN C 73 28.975 −98.561 −34.369 1.00 240.93 ATOM 862 CG ASN C 73 29.894 −97.803 −35.296 1.00 259.01 ATOM 863 OD1 ASN C 73 30.422 −98.298 −36.304 1.00 258.99 ATOM 864 ND2 ASN C 73 30.081 −96.537 −34.969 1.00 244.98 ATOM 865 N SER C 74 28.844 −100.217 −37.134 1.00 246.95 ATOM 866 CA SER C 74 28.370 −100.269 −38.506 1.00 250.11 ATOM 867 C SER C 74 27.572 −101.531 −38.832 1.00 250.27 ATOM 868 O SER C 74 26.728 −101.487 −39.722 1.00 251.48 ATOM 869 CB SER C 74 29.515 −100.050 −39.483 1.00 261.26 ATOM 870 OG SER C 74 30.453 −101.109 −39.403 1.00 272.17 ATOM 871 N LYS C 75 27.798 −102.629 −38.098 1.00 242.24 ATOM 872 CA LYS C 75 27.064 −103.861 −38.344 1.00 240.07 ATOM 873 C LYS C 75 25.964 −104.093 −37.336 1.00 239.90 ATOM 874 O LYS C 75 25.338 −105.151 −37.368 1.00 239.13 ATOM 875 CB LYS C 75 28.013 −105.061 −38.428 1.00 243.44 ATOM 876 CG LYS C 75 29.052 −104.909 −39.534 1.00 256.59 ATOM 877 CD LYS C 75 29.412 −106.230 −40.217 1.00 262.20 ATOM 878 CE LYS C 75 28.518 −106.519 −41.400 1.00 264.12 ATOM 879 NZ LYS C 75 29.037 −107.644 −42.223 1.00 269.50 ATOM 880 N SER C 76 25.691 −103.101 −36.461 1.00 234.10 ATOM 881 CA SER C 76 24.652 −103.195 −35.421 1.00 228.87 ATOM 882 C SER C 76 24.774 −104.497 −34.630 1.00 228.56 ATOM 883 O SER C 76 23.788 −105.207 −34.406 1.00 224.53 ATOM 884 CB SER C 76 23.257 −103.065 −36.023 1.00 233.29 ATOM 885 OG SER C 76 23.003 −101.731 −36.424 1.00 245.47 ATOM 886 N GLN C 77 26.003 −104.829 −34.253 1.00 226.00 ATOM 887 CA GLN C 77 26.237 −106.046 −33.523 1.00 223.85 ATOM 888 C GLN C 77 27.031 −105.784 −32.275 1.00 226.91 ATOM 889 O GLN C 77 27.928 −104.939 −32.262 1.00 226.07 ATOM 890 CB GLN C 77 26.960 −107.060 −34.402 1.00 229.27 ATOM 891 CG GLN C 77 26.138 −107.607 −35.554 1.00 250.74 ATOM 892 CD GLN C 77 26.943 −108.494 −36.491 1.00 275.75 ATOM 893 OE1 GLN C 77 26.953 −108.294 −37.707 1.00 273.34 ATOM 894 NE2 GLN C 77 27.661 −109.490 −35.970 1.00 269.24 ATOM 895 N VAL C 78 26.692 −106.521 −31.219 1.00 224.87 ATOM 896 CA VAL C 78 27.355 −106.458 −29.915 1.00 225.43 ATOM 897 C VAL C 78 27.853 −107.862 −29.587 1.00 232.32 ATOM 898 O VAL C 78 27.072 −108.817 −29.631 1.00 229.97 ATOM 899 CB VAL C 78 26.404 −105.933 −28.815 1.00 226.53 ATOM 900 CG1 VAL C 78 27.051 −106.040 −27.434 1.00 225.19 ATOM 901 CG2 VAL C 78 25.968 −104.501 −29.107 1.00 226.70 ATOM 902 N PHE C 79 29.123 −107.986 −29.219 1.00 233.57 ATOM 903 CA PHE C 79 29.692 −109.291 −28.958 1.00 235.73 ATOM 904 C PHE C 79 30.024 −109.597 −27.522 1.00 238.72 ATOM 905 O PHE C 79 30.839 −108.907 −26.917 1.00 238.58 ATOM 906 CB PHE C 79 30.916 −109.522 −29.850 1.00 243.11 ATOM 907 CG PHE C 79 30.755 −109.061 −31.283 1.00 248.87 ATOM 908 CD2 PHE C 79 31.393 −107.912 −31.737 1.00 255.03 ATOM 909 CD1 PHE C 79 30.003 −109.805 −32.195 1.00 253.44 ATOM 910 CE2 PHE C 79 31.262 −107.494 −33.073 1.00 261.66 ATOM 911 CE1 PHE C 79 29.881 −109.392 −33.531 1.00 258.18 ATOM 912 CZ PHE C 79 30.507 −108.233 −33.956 1.00 260.39 ATOM 913 N LEU C 80 29.418 −110.664 −26.986 1.00 234.81 ATOM 914 CA LEU C 80 29.722 −111.169 −25.651 1.00 233.82 ATOM 915 C LEU C 80 30.682 −112.344 −25.836 1.00 242.87 ATOM 916 O LEU C 80 30.466 −113.191 −26.705 1.00 243.95 ATOM 917 CB LEU C 80 28.457 −111.658 −24.899 1.00 230.61 ATOM 918 CG LEU C 80 28.694 −112.361 −23.538 1.00 233.90 ATOM 919 CD1 LEU C 80 27.610 −112.028 −22.559 1.00 230.90 ATOM 920 CD2 LEU C 80 28.829 −113.901 −23.693 1.00 238.76 ATOM 921 N LYS C 81 31.717 −112.418 −25.010 1.00 241.69 ATOM 922 CA LYS C 81 32.587 −113.585 −25.005 1.00 243.98 ATOM 923 C LYS C 81 32.888 −113.890 −23.569 1.00 247.67 ATOM 924 O LYS C 81 33.272 −112.979 −22.842 1.00 246.97 ATOM 925 CB LYS C 81 33.874 −113.409 −25.824 1.00 249.57 ATOM 926 CG LYS C 81 34.760 −114.669 −25.809 1.00 257.00 ATOM 927 CD LYS C 81 36.116 −114.393 −25.125 1.00 265.30 ATOM 928 CE LYS C 81 37.313 −115.029 −25.808 1.00 276.15 ATOM 929 NZ LYS C 81 38.596 −114.437 −25.339 1.00 283.50 ATOM 930 N MET C 82 32.695 −115.144 −23.138 1.00 244.94 ATOM 931 CA MET C 82 33.009 −115.524 −21.758 1.00 245.29 ATOM 932 C MET C 82 33.949 −116.755 −21.730 1.00 256.44 ATOM 933 O MET C 82 33.651 −117.777 −22.348 1.00 257.84 ATOM 934 CB MET C 82 31.733 −115.766 −20.949 1.00 244.29 ATOM 935 CG MET C 82 31.873 −115.514 −19.470 1.00 247.03 ATOM 936 SD MET C 82 30.220 −115.625 −18.710 1.00 248.41 ATOM 937 CE MET C 82 30.256 −117.297 −18.099 1.00 247.48 ATOM 938 N ASN C 83 35.090 −116.647 −21.032 1.00 256.50 ATOM 939 CA ASN C 83 36.045 −117.752 −20.963 1.00 260.34 ATOM 940 C ASN C 83 35.620 −118.843 −19.985 1.00 265.37 ATOM 941 O ASN C 83 34.852 −118.570 −19.054 1.00 263.30 ATOM 942 CB ASN C 83 37.495 −117.231 −20.789 1.00 262.96 ATOM 943 CG ASN C 83 38.302 −117.623 −19.576 1.00 280.41 ATOM 944 OD1 ASN C 83 38.523 −118.796 −19.292 1.00 272.90 ATOM 945 ND2 ASN C 83 38.946 −116.640 −18.968 1.00 274.23 ATOM 946 N SER C 84 36.130 −120.079 −20.229 1.00 264.80 ATOM 947 CA SER C 84 35.975 −121.326 −19.463 1.00 265.99 ATOM 948 C SER C 84 34.686 −121.504 −18.671 1.00 267.85 ATOM 949 O SER C 84 34.660 −121.398 −17.435 1.00 266.84 ATOM 950 CB SER C 84 37.208 −121.585 −18.600 1.00 271.28 ATOM 951 OG SER C 84 37.267 −122.867 −17.995 1.00 276.69 ATOM 952 N LEU C 85 33.623 −121.818 −19.393 1.00 264.45 ATOM 953 CA LEU C 85 32.332 −122.057 −18.783 1.00 263.47 ATOM 954 C LEU C 85 32.335 −123.345 −17.981 1.00 271.20 ATOM 955 O LEU C 85 33.112 −124.269 −18.253 1.00 273.51 ATOM 956 CB LEU C 85 31.220 −122.058 −19.851 1.00 262.03 ATOM 957 CG LEU C 85 30.673 −120.656 −20.147 1.00 263.64 ATOM 958 CD1 LEU C 85 31.672 −119.863 −20.959 1.00 264.04 ATOM 959 CD2 LEU C 85 29.310 −120.704 −20.833 1.00 265.31 ATOM 960 N GLN C 86 31.508 −123.358 −16.943 1.00 267.03 ATOM 961 CA GLN C 86 31.287 −124.505 −16.099 1.00 269.78 ATOM 962 C GLN C 86 29.789 −124.747 −16.095 1.00 273.22 ATOM 963 O GLN C 86 29.027 −123.922 −16.611 1.00 270.26 ATOM 964 CB GLN C 86 31.837 −124.252 −14.695 1.00 271.53 ATOM 965 CG GLN C 86 33.326 −124.496 −14.615 1.00 273.60 ATOM 966 CD GLN C 86 33.602 −125.984 −14.614 1.00 277.19 ATOM 967 OE1 GLN C 86 33.485 −126.691 −13.604 1.00 274.74 ATOM 968 NE2 GLN C 86 33.846 −126.506 −15.776 1.00 263.98 ATOM 969 N THR C 87 29.365 −125.885 −15.552 1.00 271.67 ATOM 970 CA THR C 87 27.956 −126.270 −15.500 1.00 271.98 ATOM 971 C THR C 87 27.063 −125.152 −14.924 1.00 271.97 ATOM 972 O THR C 87 25.992 −124.906 −15.470 1.00 270.41 ATOM 973 CB THR C 87 27.800 −127.632 −14.807 1.00 279.45 ATOM 974 OG1 THR C 87 28.146 −127.493 −13.430 1.00 281.11 ATOM 975 CG2 THR C 87 28.667 −128.720 −15.448 1.00 276.94 ATOM 976 N ASP C 88 27.531 −124.426 −13.889 1.00 266.30 ATOM 977 CA ASP C 88 26.749 −123.336 −13.286 1.00 263.24 ATOM 978 C ASP C 88 26.565 −122.060 −14.159 1.00 261.40 ATOM 979 O ASP C 88 25.907 −121.102 −13.729 1.00 258.59 ATOM 980 CB ASP C 88 27.260 −123.010 −11.876 1.00 266.30 ATOM 981 CG ASP C 88 28.689 −122.511 −11.799 1.00 270.13 ATOM 982 OD1 ASP C 88 29.060 −121.940 −10.753 1.00 270.87 ATOM 983 OD2 ASP C 88 29.429 −122.651 −12.801 1.00 271.67 ATOM 984 N ASP C 89 27.134 −122.059 −15.378 1.00 255.73 ATOM 985 CA ASP C 89 26.984 −120.966 −16.333 1.00 251.01 ATOM 986 C ASP C 89 25.844 −121.318 −17.295 1.00 251.67 ATOM 987 O ASP C 89 25.564 −120.570 −18.237 1.00 248.94 ATOM 988 CB ASP C 89 28.305 −120.694 −17.067 1.00 252.62 ATOM 989 CG ASP C 89 29.403 −120.153 −16.155 1.00 266.29 ATOM 990 OD1 ASP C 89 29.172 −119.102 −15.500 1.00 265.27 ATOM 991 OD2 ASP C 89 30.489 −120.793 −16.080 1.00 276.06 ATOM 992 N THR C 90 25.174 −122.469 −17.042 1.00 248.92 ATOM 993 CA THR C 90 24.002 −122.911 −17.812 1.00 247.97 ATOM 994 C THR C 90 22.870 −121.925 −17.475 1.00 249.05 ATOM 995 O THR C 90 22.477 −121.802 −16.301 1.00 249.29 ATOM 996 CB THR C 90 23.603 −124.360 −17.478 1.00 250.67 ATOM 997 OG1 THR C 90 24.607 −125.263 −17.958 1.00 250.51 ATOM 998 CG2 THR C 90 22.234 −124.736 −18.049 1.00 245.32 ATOM 999 N ALA C 91 22.377 −121.204 −18.497 1.00 242.43 ATOM 1000 CA ALA C 91 21.361 −120.170 −18.301 1.00 239.45 ATOM 1001 C ALA C 91 20.873 −119.660 −19.635 1.00 238.56 ATOM 1002 O ALA C 91 21.449 −119.988 −20.679 1.00 238.92 ATOM 1003 CB ALA C 91 21.971 −118.994 −17.520 1.00 237.93 ATOM 1004 N ARG C 92 19.802 −118.849 −19.602 1.00 230.17 ATOM 1005 CA ARG C 92 19.322 −118.170 −20.794 1.00 226.08 ATOM 1006 C ARG C 92 20.026 −116.823 −20.723 1.00 222.86 ATOM 1007 O ARG C 92 20.020 −116.167 −19.670 1.00 220.46 ATOM 1008 CB ARG C 92 17.784 −118.026 −20.829 1.00 225.00 ATOM 1009 CG ARG C 92 17.289 −117.250 −22.059 1.00 226.42 ATOM 1010 CD ARG C 92 15.793 −117.357 −22.301 1.00 234.80 ATOM 1011 NE ARG C 92 15.512 −118.553 −23.095 1.00 251.51 ATOM 1012 CZ ARG C 92 15.197 −118.564 −24.391 1.00 267.75 ATOM 1013 NH1 ARG C 92 15.037 −117.428 −25.052 1.00 257.16 ATOM 1014 NH2 ARG C 92 15.020 −119.716 −25.028 1.00 253.47 ATOM 1015 N TYR C 93 20.680 −116.449 −21.824 1.00 216.93 ATOM 1016 CA TYR C 93 21.434 −115.204 −21.948 1.00 214.66 ATOM 1017 C TYR C 93 20.673 −114.201 −22.815 1.00 213.82 ATOM 1018 O TYR C 93 20.343 −114.534 −23.958 1.00 216.93 ATOM 1019 CB TYR C 93 22.819 −115.487 −22.560 1.00 217.89 ATOM 1020 CG TYR C 93 23.764 −116.172 −21.593 1.00 224.05 ATOM 1021 CD1 TYR C 93 23.539 −117.483 −21.174 1.00 228.47 ATOM 1022 CD2 TYR C 93 24.869 −115.500 −21.069 1.00 225.63 ATOM 1023 CE1 TYR C 93 24.384 −118.109 −20.254 1.00 231.23 ATOM 1024 CE2 TYR C 93 25.714 −116.111 −20.132 1.00 228.61 ATOM 1025 CZ TYR C 93 25.476 −117.422 −19.741 1.00 240.55 ATOM 1026 OH TYR C 93 26.320 −118.047 −18.849 1.00 247.46 ATOM 1027 N TYR C 94 20.410 −112.979 −22.292 1.00 201.12 ATOM 1028 CA TYR C 94 19.705 −111.924 −23.018 1.00 196.10 ATOM 1029 C TYR C 94 20.589 −110.707 −23.249 1.00 201.56 ATOM 1030 O TYR C 94 21.357 −110.326 −22.362 1.00 201.70 ATOM 1031 CB TYR C 94 18.552 −111.380 −22.193 1.00 193.18 ATOM 1032 CG TYR C 94 17.563 −112.363 −21.653 1.00 192.67 ATOM 1033 CD1 TYR C 94 16.364 −112.598 −22.310 1.00 196.13 ATOM 1034 CD2 TYR C 94 17.752 −112.949 −20.414 1.00 193.31 ATOM 1035 CE1 TYR C 94 15.399 −113.442 −21.776 1.00 199.62 ATOM 1036 CE2 TYR C 94 16.801 −113.798 −19.868 1.00 196.58 ATOM 1037 CZ TYR C 94 15.617 −114.033 −20.547 1.00 206.72 ATOM 1038 OH TYR C 94 14.663 −114.861 −20.014 1.00 212.42 ATOM 1039 N CYS C 95 20.421 −110.038 −24.389 1.00 199.59 ATOM 1040 CA CYS C 95 21.031 −108.734 −24.582 1.00 199.61 ATOM 1041 C CYS C 95 19.830 −107.782 −24.474 1.00 200.06 ATOM 1042 O CYS C 95 18.727 −108.112 −24.914 1.00 201.62 ATOM 1043 CB CYS C 95 21.799 −108.585 −25.892 1.00 202.87 ATOM 1044 SG CYS C 95 20.826 −108.864 −27.388 1.00 209.82 ATOM 1045 N ALA C 96 19.998 −106.683 −23.756 1.00 192.01 ATOM 1046 CA ALA C 96 18.921 −105.732 −23.499 1.00 189.07 ATOM 1047 C ALA C 96 19.449 −104.350 −23.728 1.00 189.32 ATOM 1048 O ALA C 96 20.592 −104.057 −23.348 1.00 189.59 ATOM 1049 CB ALA C 96 18.488 −105.856 −22.064 1.00 189.10 ATOM 1050 N ARG C 97 18.632 −103.487 −24.334 1.00 182.19 ATOM 1051 CA ARG C 97 19.062 −102.103 −24.576 1.00 180.60 ATOM 1052 C ARG C 97 18.861 −101.242 −23.336 1.00 181.37 ATOM 1053 O ARG C 97 17.965 −101.488 −22.544 1.00 180.82 ATOM 1054 CB ARG C 97 18.250 −101.471 −25.722 1.00 178.25 ATOM 1055 CG ARG C 97 18.748 −100.083 −26.143 1.00 174.95 ATOM 1056 CD ARG C 97 17.874 −99.442 −27.197 1.00 180.01 ATOM 1057 NE ARG C 97 16.659 −98.785 −26.692 1.00 184.42 ATOM 1058 CZ ARG C 97 15.915 −97.945 −27.425 1.00 194.45 ATOM 1059 NH1 ARG C 97 16.282 −97.620 −28.658 1.00 183.13 ATOM 1060 NH2 ARG C 97 14.803 −97.431 −26.932 1.00 173.66 ATOM 1061 N ASP C 98 19.669 −100.222 −23.181 1.00 176.02 ATOM 1062 CA ASP C 98 19.426 −99.269 −22.137 1.00 175.16 ATOM 1063 C ASP C 98 19.684 −97.885 −22.752 1.00 175.24 ATOM 1064 O ASP C 98 20.704 −97.699 −23.453 1.00 175.80 ATOM 1065 CB ASP C 98 20.189 −99.565 −20.815 1.00 177.83 ATOM 1066 CG ASP C 98 21.662 −99.145 −20.705 1.00 200.06 ATOM 1067 OD2 ASP C 98 22.240 −99.294 −19.618 1.00 208.72 ATOM 1068 OD1 ASP C 98 22.262 −98.776 −21.730 1.00 203.84 ATOM 1069 N PRO C 99 18.642 −97.005 −22.654 1.00 165.90 ATOM 1070 CA PRO C 99 18.760 −95.621 −23.124 1.00 165.12 ATOM 1071 C PRO C 99 19.373 −94.720 −22.025 1.00 166.32 ATOM 1072 O PRO C 99 18.968 −93.577 −21.809 1.00 166.08 ATOM 1073 CB PRO C 99 17.312 −95.253 −23.410 1.00 166.93 ATOM 1074 CG PRO C 99 16.489 −96.305 −22.745 1.00 170.01 ATOM 1075 CD PRO C 99 17.351 −97.194 −21.981 1.00 165.23 ATOM 1076 N TYR C 100 20.394 −95.261 −21.363 1.00 161.73 ATOM 1077 CA TYR C 100 21.175 −94.747 −20.251 1.00 162.93 ATOM 1078 C TYR C 100 20.868 −93.384 −19.584 1.00 169.39 ATOM 1079 O TYR C 100 20.686 −93.364 −18.367 1.00 172.49 ATOM 1080 CB TYR C 100 22.681 −95.007 −20.397 1.00 164.59 ATOM 1081 CG TYR C 100 23.358 −94.615 −21.696 1.00 165.93 ATOM 1082 CD1 TYR C 100 23.433 −95.509 −22.763 1.00 166.41 ATOM 1083 CD2 TYR C 100 24.097 −93.442 −21.787 1.00 169.01 ATOM 1084 CE1 TYR C 100 24.167 −95.210 −23.909 1.00 167.90 ATOM 1085 CE2 TYR C 100 24.875 −93.162 −22.907 1.00 171.74 ATOM 1086 CZ TYR C 100 24.873 −94.026 −23.983 1.00 177.51 ATOM 1087 OH TYR C 100 25.562 −93.696 −25.118 1.00 182.67 ATOM 1088 N GLY C 101 20.847 −92.283 −20.310 1.00 163.55 ATOM 1089 CA GLY C 101 20.574 −91.011 −19.653 1.00 164.92 ATOM 1090 C GLY C 101 19.107 −90.784 −19.369 1.00 167.63 ATOM 1091 O GLY C 101 18.739 −90.153 −18.378 1.00 166.91 ATOM 1092 N SER C 102 18.268 −91.302 −20.256 1.00 165.55 ATOM 1093 CA SER C 102 16.822 −91.143 −20.212 1.00 167.29 ATOM 1094 C SER C 102 16.096 −92.319 −19.550 1.00 172.53 ATOM 1095 O SER C 102 15.123 −92.077 −18.846 1.00 175.22 ATOM 1096 CB SER C 102 16.252 −90.940 −21.621 1.00 171.37 ATOM 1097 OG SER C 102 16.746 −89.824 −22.345 1.00 179.02 ATOM 1098 N LYS C 103 16.473 −93.579 −19.830 1.00 166.61 ATOM 1099 CA LYS C 103 15.727 −94.701 −19.258 1.00 165.71 ATOM 1100 C LYS C 103 16.587 −95.920 −18.895 1.00 173.62 ATOM 1101 O LYS C 103 17.725 −96.054 −19.356 1.00 172.00 ATOM 1102 CB LYS C 103 14.628 −95.164 −20.247 1.00 165.32 ATOM 1103 CG LYS C 103 13.422 −94.248 −20.443 1.00 159.19 ATOM 1104 CD LYS C 103 12.208 −94.987 −21.035 1.00 161.03 ATOM 1105 CE LYS C 103 12.270 −95.294 −22.524 1.00 169.31 ATOM 1106 NZ LYS C 103 11.529 −96.550 −22.887 1.00 176.67 ATOM 1107 N PRO C 104 16.020 −96.872 −18.129 1.00 175.22 ATOM 1108 CA PRO C 104 16.725 −98.133 −17.872 1.00 175.64 ATOM 1109 C PRO C 104 16.303 −99.197 −18.915 1.00 182.32 ATOM 1110 O PRO C 104 15.294 −98.982 −19.604 1.00 182.87 ATOM 1111 CB PRO C 104 16.232 −98.515 −16.481 1.00 178.75 ATOM 1112 CG PRO C 104 14.874 −97.950 −16.421 1.00 184.39 ATOM 1113 CD PRO C 104 14.702 −96.886 −17.476 1.00 179.12 ATOM 1114 N MET C 105 17.053 −100.347 −19.008 1.00 179.04 ATOM 1115 CA MET C 105 16.848 −101.463 −19.949 1.00 177.87 ATOM 1116 C MET C 105 15.411 −101.597 −20.432 1.00 186.09 ATOM 1117 O MET C 105 14.582 −102.250 −19.805 1.00 187.73 ATOM 1118 CB MET C 105 17.341 −102.820 −19.411 1.00 179.30 ATOM 1119 CG MET C 105 18.828 −102.970 −19.275 1.00 181.80 ATOM 1120 SD MET C 105 19.064 −104.640 −18.631 1.00 185.03 ATOM 1121 CE MET C 105 20.457 −104.448 −17.762 1.00 181.47 ATOM 1122 N ASP C 106 15.125 −100.916 −21.534 1.00 184.24 ATOM 1123 CA ASP C 106 13.870 −100.879 −22.279 1.00 185.24 ATOM 1124 C ASP C 106 14.137 −101.801 −23.481 1.00 191.65 ATOM 1125 O ASP C 106 15.167 −101.621 −24.133 1.00 192.61 ATOM 1126 CB ASP C 106 13.658 −99.416 −22.744 1.00 186.84 ATOM 1127 CG ASP C 106 14.565 −98.886 −23.866 1.00 181.60 ATOM 1128 OD1 ASP C 106 15.805 −99.142 −23.825 1.00 178.19 ATOM 1129 OD2 ASP C 106 14.043 −98.214 −24.768 1.00 181.40 ATOM 1130 N TYR C 107 13.314 −102.789 −23.783 1.00 189.18 ATOM 1131 CA TYR C 107 13.700 −103.653 −24.910 1.00 190.12 ATOM 1132 C TYR C 107 14.765 −104.731 −24.640 1.00 197.98 ATOM 1133 O TYR C 107 15.998 −104.528 −24.660 1.00 195.18 ATOM 1134 CB TYR C 107 13.993 −102.915 −26.218 1.00 191.38 ATOM 1135 CG TYR C 107 12.870 −102.025 −26.638 1.00 194.83 ATOM 1136 CD2 TYR C 107 11.736 −102.551 −27.237 1.00 196.86 ATOM 1137 CD1 TYR C 107 12.979 −100.643 −26.537 1.00 198.02 ATOM 1138 CE2 TYR C 107 10.724 −101.730 −27.714 1.00 199.52 ATOM 1139 CE1 TYR C 107 11.958 −99.807 −26.984 1.00 202.06 ATOM 1140 CZ TYR C 107 10.830 −100.359 −27.580 1.00 207.92 ATOM 1141 OH TYR C 107 9.795 −99.579 −28.052 1.00 208.83 ATOM 1142 N TRP C 108 14.224 −105.927 −24.477 1.00 200.80 ATOM 1143 CA TRP C 108 14.953 −107.163 −24.240 1.00 202.32 ATOM 1144 C TRP C 108 14.886 −108.068 −25.451 1.00 211.97 ATOM 1145 O TRP C 108 13.849 −108.159 −26.126 1.00 213.65 ATOM 1146 CB TRP C 108 14.303 −107.917 −23.083 1.00 201.78 ATOM 1147 CG TRP C 108 14.445 −107.225 −21.780 1.00 202.06 ATOM 1148 CD1 TRP C 108 13.941 −106.006 −21.431 1.00 205.01 ATOM 1149 CD2 TRP C 108 15.128 −107.725 −20.637 1.00 201.85 ATOM 1150 NE1 TRP C 108 14.301 −105.703 −20.148 1.00 204.54 ATOM 1151 CE2 TRP C 108 15.023 −106.749 −19.628 1.00 205.93 ATOM 1152 CE3 TRP C 108 15.861 −108.892 −20.376 1.00 203.48 ATOM 1153 CZ2 TRP C 108 15.630 −106.907 −18.374 1.00 205.77 ATOM 1154 CZ3 TRP C 108 16.432 −109.064 −19.124 1.00 205.24 ATOM 1155 CH2 TRP C 108 16.313 −108.082 −18.139 1.00 205.99 ATOM 1156 N GLY C 109 15.973 −108.780 −25.693 1.00 210.90 ATOM 1157 CA GLY C 109 15.972 −109.799 −26.731 1.00 213.51 ATOM 1158 C GLY C 109 15.179 −110.970 −26.175 1.00 221.08 ATOM 1159 O GLY C 109 14.909 −111.008 −24.964 1.00 221.60 ATOM 1160 N GLN C 110 14.777 −111.918 −27.022 1.00 219.60 ATOM 1161 CA GLN C 110 14.029 −113.082 −26.547 1.00 221.61 ATOM 1162 C GLN C 110 14.922 −113.982 −25.668 1.00 226.47 ATOM 1163 O GLN C 110 14.406 −114.755 −24.866 1.00 226.50 ATOM 1164 CB GLN C 110 13.495 −113.870 −27.739 1.00 225.94 ATOM 1165 CG GLN C 110 14.631 −114.468 −28.572 1.00 249.21 ATOM 1166 CD GLN C 110 14.251 −114.911 −29.963 1.00 273.76 ATOM 1167 OE1 GLN C 110 13.080 −114.885 −30.379 1.00 271.32 ATOM 1168 NE2 GLN C 110 15.253 −115.281 −30.750 1.00 266.05 ATOM 1169 N GLY C 111 16.242 −113.869 −25.833 1.00 224.51 ATOM 1170 CA GLY C 111 17.200 −114.674 −25.091 1.00 225.89 ATOM 1171 C GLY C 111 17.631 −115.917 −25.837 1.00 235.97 ATOM 1172 O GLY C 111 16.908 −116.399 −26.713 1.00 237.63 ATOM 1173 N THR C 112 18.826 −116.429 −25.518 1.00 235.92 ATOM 1174 CA THR C 112 19.336 −117.681 −26.099 1.00 240.05 ATOM 1175 C THR C 112 19.712 −118.612 −24.960 1.00 244.66 ATOM 1176 O THR C 112 20.446 −118.205 −24.041 1.00 243.52 ATOM 1177 CB THR C 112 20.515 −117.503 −27.120 1.00 258.42 ATOM 1178 OG1 THR C 112 20.789 −118.785 −27.727 1.00 264.47 ATOM 1179 CG2 THR C 112 21.811 −116.938 −26.465 1.00 257.47 ATOM 1180 N SER C 113 19.217 −119.858 −25.018 1.00 241.67 ATOM 1181 CA SER C 113 19.515 −120.831 −23.984 1.00 241.49 ATOM 1182 C SER C 113 20.902 −121.445 −24.186 1.00 243.68 ATOM 1183 O SER C 113 21.243 −121.869 −25.291 1.00 245.11 ATOM 1184 CB SER C 113 18.419 −121.884 −23.915 1.00 247.36 ATOM 1185 OG SER C 113 18.870 −123.025 −23.204 1.00 257.84 ATOM 1186 N VAL C 114 21.711 −121.441 −23.118 1.00 237.59 ATOM 1187 CA VAL C 114 23.071 −121.977 −23.119 1.00 237.75 ATOM 1188 C VAL C 114 23.148 −123.117 −22.117 1.00 245.35 ATOM 1189 O VAL C 114 22.818 −122.935 −20.936 1.00 244.72 ATOM 1190 CB VAL C 114 24.157 −120.900 −22.834 1.00 237.73 ATOM 1191 CG1 VAL C 114 25.552 −121.521 −22.777 1.00 239.20 ATOM 1192 CG2 VAL C 114 24.127 −119.808 −23.889 1.00 235.25 ATOM 1193 N THR C 115 23.612 −124.287 −22.593 1.00 244.93 ATOM 1194 CA THR C 115 23.787 −125.468 −21.759 1.00 247.53 ATOM 1195 C THR C 115 25.256 −125.809 −21.719 1.00 249.43 ATOM 1196 O THR C 115 25.887 −125.925 −22.768 1.00 249.03 ATOM 1197 CB THR C 115 22.966 −126.641 −22.298 1.00 263.16 ATOM 1198 OG1 THR C 115 21.616 −126.209 −22.474 1.00 263.76 ATOM 1199 CG2 THR C 115 23.025 −127.876 −21.380 1.00 266.71 ATOM 1200 N VAL C 116 25.801 −125.966 −20.522 1.00 244.82 ATOM 1201 CA VAL C 116 27.200 −126.316 −20.410 1.00 245.14 ATOM 1202 C VAL C 116 27.260 −127.766 −19.981 1.00 255.05 ATOM 1203 O VAL C 116 26.842 −128.094 −18.864 1.00 256.45 ATOM 1204 CB VAL C 116 27.990 −125.376 −19.487 1.00 245.20 ATOM 1205 CG1 VAL C 116 29.472 −125.731 −19.514 1.00 246.44 ATOM 1206 CG2 VAL C 116 27.775 −123.923 −19.893 1.00 240.81 ATOM 1207 N SER C 117 27.743 −128.641 −20.890 1.00 254.39 ATOM 1208 CA SER C 117 27.864 −130.090 −20.678 1.00 256.49 ATOM 1209 C SER C 117 28.654 −130.757 −21.818 1.00 258.43 ATOM 1210 O SER C 117 28.888 −130.140 −22.853 1.00 257.63 ATOM 1211 CB SER C 117 26.481 −130.736 −20.571 1.00 259.10 ATOM 1212 OG SER C 117 26.604 −132.124 −20.286 1.00 263.70 ATOM 1213 N SER C 118 29.029 −132.034 −21.655 1.00 256.05 ATOM 1214 CA SER C 118 29.692 −132.806 −22.714 1.00 253.96 ATOM 1215 C SER C 118 28.846 −134.065 −23.045 1.00 238.13 ATOM 1216 O SER C 118 28.463 −134.337 −24.201 1.00 176.20 ATOM 1217 CB SER C 118 31.111 −133.183 −22.298 1.00 256.18 ATOM 1218 OG SER C 118 31.113 −133.869 −21.057 1.00 261.64 ATOM 1220 N ASP D 1 30.700 −101.896 −5.650 1.00 219.75 ATOM 1221 CA ASP D 1 29.635 −102.694 −6.264 1.00 215.21 ATOM 1222 C ASP D 1 28.358 −102.601 −5.407 1.00 214.43 ATOM 1223 O ASP D 1 28.441 −102.803 −4.193 1.00 215.39 ATOM 1224 CB ASP D 1 30.091 −104.167 −6.442 1.00 218.57 ATOM 1225 CG ASP D 1 29.804 −104.786 −7.813 1.00 226.38 ATOM 1226 OD2 ASP D 1 28.649 −105.237 −8.040 1.00 230.15 ATOM 1227 OD1 ASP D 1 30.740 −104.856 −8.641 1.00 228.29 ATOM 1228 N ILE D 2 27.195 −102.275 −6.017 1.00 205.37 ATOM 1229 CA ILE D 2 25.953 −102.154 −5.255 1.00 200.95 ATOM 1230 C ILE D 2 25.204 −103.475 −5.202 1.00 202.02 ATOM 1231 O ILE D 2 24.984 −104.107 −6.239 1.00 200.75 ATOM 1232 CB ILE D 2 25.053 −100.996 −5.756 1.00 200.66 ATOM 1233 CG1 ILE D 2 25.840 −99.675 −5.865 1.00 203.17 ATOM 1234 CG2 ILE D 2 23.801 −100.850 −4.889 1.00 198.20 ATOM 1235 CD1 ILE D 2 25.003 −98.430 −6.360 1.00 207.75 ATOM 1236 N VAL D 3 24.790 −103.875 −3.995 1.00 197.39 ATOM 1237 CA VAL D 3 24.013 −105.091 −3.790 1.00 195.24 ATOM 1238 C VAL D 3 22.529 −104.776 −3.572 1.00 192.85 ATOM 1239 O VAL D 3 22.185 −103.909 −2.767 1.00 191.33 ATOM 1240 CB VAL D 3 24.583 −105.958 −2.656 1.00 202.47 ATOM 1241 CG1 VAL D 3 23.638 −107.107 −2.309 1.00 201.27 ATOM 1242 CG2 VAL D 3 25.955 −106.497 −3.033 1.00 205.65 ATOM 1243 N MET D 4 21.666 −105.532 −4.263 1.00 185.60 ATOM 1244 CA MET D 4 20.226 −105.403 −4.185 1.00 182.08 ATOM 1245 C MET D 4 19.599 −106.622 −3.561 1.00 183.32 ATOM 1246 O MET D 4 19.931 −107.740 −3.930 1.00 184.69 ATOM 1247 CB MET D 4 19.639 −105.223 −5.581 1.00 183.09 ATOM 1248 CG MET D 4 20.292 −104.135 −6.416 1.00 188.24 ATOM 1249 SD MET D 4 20.260 −102.506 −5.653 1.00 194.21 ATOM 1250 CE MET D 4 18.473 −102.165 −5.632 1.00 187.91 ATOM 1251 N SER D 5 18.666 −106.421 −2.653 1.00 178.23 ATOM 1252 CA SER D 5 17.972 −107.516 −1.995 1.00 179.45 ATOM 1253 C SER D 5 16.462 −107.305 −1.950 1.00 182.40 ATOM 1254 O SER D 5 16.004 −106.237 −1.551 1.00 181.07 ATOM 1255 CB SER D 5 18.534 −107.736 −0.592 1.00 187.61 ATOM 1256 OG SER D 5 18.639 −106.542 0.169 1.00 198.91 ATOM 1257 N GLN D 6 15.689 −108.325 −2.340 1.00 179.97 ATOM 1258 CA GLN D 6 14.234 −108.246 −2.365 1.00 179.57 ATOM 1259 C GLN D 6 13.543 −109.232 −1.426 1.00 192.26 ATOM 1260 O GLN D 6 14.034 −110.341 −1.182 1.00 192.53 ATOM 1261 CB GLN D 6 13.698 −108.472 −3.784 1.00 178.04 ATOM 1262 CG GLN D 6 14.362 −107.659 −4.879 1.00 149.98 ATOM 1263 CD GLN D 6 13.700 −107.937 −6.204 1.00 172.08 ATOM 1264 OE1 GLN D 6 14.377 −108.186 −7.194 1.00 168.54 ATOM 1265 NE2 GLN D 6 12.363 −107.888 −6.270 1.00 172.65 ATOM 1266 N SER D 7 12.363 −108.825 −0.948 1.00 195.02 ATOM 1267 CA SER D 7 11.482 −109.616 −0.088 1.00 199.12 ATOM 1268 C SER D 7 10.018 −109.289 −0.459 1.00 204.12 ATOM 1269 O SER D 7 9.722 −108.146 −0.806 1.00 203.72 ATOM 1270 CB SER D 7 11.762 −109.345 1.384 1.00 206.38 ATOM 1271 OG SER D 7 11.483 −107.991 1.694 1.00 218.81 ATOM 1272 N PRO D 8 9.101 −110.262 −0.440 1.00 201.18 ATOM 1273 CA PRO D 8 9.320 −111.656 −0.101 1.00 203.06 ATOM 1274 C PRO D 8 10.019 −112.312 −1.282 1.00 206.04 ATOM 1275 O PRO D 8 10.160 −111.701 −2.344 1.00 203.51 ATOM 1276 CB PRO D 8 7.888 −112.168 0.101 1.00 206.78 ATOM 1277 CG PRO D 8 7.122 −111.418 −0.918 1.00 209.40 ATOM 1278 CD PRO D 8 7.712 −110.036 −0.881 1.00 202.71 ATOM 1279 N SER D 9 10.451 −113.552 −1.092 1.00 202.99 ATOM 1280 CA SER D 9 11.048 −114.348 −2.141 1.00 201.21 ATOM 1281 C SER D 9 9.855 −114.770 −3.033 1.00 205.09 ATOM 1282 O SER D 9 10.017 −114.981 −4.237 1.00 203.20 ATOM 1283 CB SER D 9 11.719 −115.558 −1.510 1.00 205.36 ATOM 1284 OG SER D 9 12.059 −115.332 −0.145 1.00 210.14 ATOM 1285 N SER D 10 8.637 −114.811 −2.415 1.00 203.61 ATOM 1286 CA SER D 10 7.360 −115.151 −3.040 1.00 204.25 ATOM 1287 C SER D 10 6.149 −114.874 −2.123 1.00 207.98 ATOM 1288 O SER D 10 6.298 −114.788 −0.907 1.00 208.80 ATOM 1289 CB SER D 10 7.369 −116.613 −3.475 1.00 210.49 ATOM 1290 OG SER D 10 7.631 −117.478 −2.382 1.00 220.56 ATOM 1291 N LEU D 11 4.948 −114.768 −2.713 1.00 203.36 ATOM 1292 CA LEU D 11 3.687 −114.551 −1.995 1.00 204.47 ATOM 1293 C LEU D 11 2.507 −114.921 −2.888 1.00 209.45 ATOM 1294 O LEU D 11 2.670 −115.019 −4.104 1.00 206.09 ATOM 1295 CB LEU D 11 3.581 −113.092 −1.507 1.00 202.35 ATOM 1296 CG LEU D 11 3.351 −111.996 −2.562 1.00 203.05 ATOM 1297 CD1 LEU D 11 2.869 −110.750 −1.921 1.00 202.20 ATOM 1298 CD2 LEU D 11 4.594 −111.735 −3.408 1.00 199.95 ATOM 1299 N VAL D 12 1.328 −115.135 −2.291 1.00 211.94 ATOM 1300 CA VAL D 12 0.114 −115.484 −3.042 1.00 216.37 ATOM 1301 C VAL D 12 −1.003 −114.502 −2.714 1.00 222.00 ATOM 1302 O VAL D 12 −1.174 −114.145 −1.547 1.00 222.49 ATOM 1303 CB VAL D 12 −0.343 −116.964 −2.846 1.00 226.79 ATOM 1304 CG1 VAL D 12 0.840 −117.947 −2.888 1.00 226.01 ATOM 1305 CG2 VAL D 12 −1.153 −117.160 −1.555 1.00 231.27 ATOM 1306 N VAL D 13 −1.767 −114.081 −3.728 1.00 219.56 ATOM 1307 CA VAL D 13 −2.882 −113.144 −3.568 1.00 221.45 ATOM 1308 C VAL D 13 −4.003 −113.475 −4.533 1.00 227.02 ATOM 1309 O VAL D 13 −3.734 −113.999 −5.617 1.00 225.91 ATOM 1310 CB VAL D 13 −2.395 −111.703 −3.798 1.00 222.09 ATOM 1311 CG1 VAL D 13 −2.148 −111.424 −5.284 1.00 219.38 ATOM 1312 CG2 VAL D 13 −3.388 −110.719 −3.228 1.00 223.91 ATOM 1313 N SER D 14 −5.241 −113.122 −4.184 1.00 226.63 ATOM 1314 CA SER D 14 −6.340 −113.380 −5.105 1.00 230.48 ATOM 1315 C SER D 14 −6.593 −112.155 −5.960 1.00 233.23 ATOM 1316 O SER D 14 −6.156 −111.064 −5.607 1.00 228.51 ATOM 1317 CB SER D 14 −7.610 −113.798 −4.359 1.00 240.15 ATOM 1318 OG SER D 14 −8.508 −114.515 −5.200 1.00 248.33 ATOM 1319 N VAL D 15 −7.309 −112.337 −7.077 1.00 234.06 ATOM 1320 CA VAL D 15 −7.701 −111.267 −8.002 1.00 233.09 ATOM 1321 C VAL D 15 −8.464 −110.147 −7.257 1.00 237.91 ATOM 1322 O VAL D 15 −9.333 −110.432 −6.433 1.00 241.55 ATOM 1323 CB VAL D 15 −8.544 −111.823 −9.178 1.00 241.51 ATOM 1324 CG1 VAL D 15 −9.008 −110.707 −10.110 1.00 240.25 ATOM 1325 CG2 VAL D 15 −7.767 −112.883 −9.950 1.00 240.83 ATOM 1326 N GLY D 16 −8.124 −108.899 −7.567 1.00 230.71 ATOM 1327 CA GLY D 16 −8.761 −107.735 −6.965 1.00 230.65 ATOM 1328 C GLY D 16 −8.015 −107.129 −5.793 1.00 230.26 ATOM 1329 O GLY D 16 −8.198 −105.942 −5.511 1.00 228.55 ATOM 1330 N GLU D 17 −7.179 −107.926 −5.093 1.00 224.41 ATOM 1331 CA GLU D 17 −6.402 −107.415 −3.963 1.00 220.79 ATOM 1332 C GLU D 17 −5.153 −106.592 −4.403 1.00 215.13 ATOM 1333 O GLU D 17 −4.641 −106.765 −5.509 1.00 212.08 ATOM 1334 CB GLU D 17 −5.991 −108.567 −3.060 1.00 224.15 ATOM 1335 CG GLU D 17 −5.896 −108.204 −1.591 1.00 236.27 ATOM 1336 CD GLU D 17 −4.958 −109.093 −0.795 1.00 263.60 ATOM 1337 OE1 GLU D 17 −5.096 −110.337 −0.864 1.00 272.93 ATOM 1338 OE2 GLU D 17 −4.036 −108.547 −0.152 1.00 251.34 ATOM 1339 N LYS D 18 −4.674 −105.701 −3.523 1.00 206.57 ATOM 1340 CA LYS D 18 −3.490 −104.891 −3.757 1.00 199.67 ATOM 1341 C LYS D 18 −2.291 −105.677 −3.263 1.00 201.92 ATOM 1342 O LYS D 18 −2.426 −106.451 −2.324 1.00 204.60 ATOM 1343 CB LYS D 18 −3.614 −103.585 −2.987 1.00 200.65 ATOM 1344 CG LYS D 18 −2.653 −102.509 −3.453 1.00 212.59 ATOM 1345 CD LYS D 18 −2.942 −101.148 −2.816 1.00 228.84 ATOM 1346 CE LYS D 18 −2.576 −99.971 −3.708 1.00 240.61 ATOM 1347 NZ LYS D 18 −3.105 −98.665 −3.214 1.00 251.85 ATOM 1348 N VAL D 19 −1.123 −105.497 −3.872 1.00 195.38 ATOM 1349 CA VAL D 19 0.098 −106.225 −3.462 1.00 195.06 ATOM 1350 C VAL D 19 1.284 −105.320 −3.344 1.00 196.89 ATOM 1351 O VAL D 19 1.477 −104.497 −4.234 1.00 196.16 ATOM 1352 CB VAL D 19 0.416 −107.323 −4.487 1.00 199.61 ATOM 1353 CG1 VAL D 19 1.876 −107.773 −4.424 1.00 197.04 ATOM 1354 CG2 VAL D 19 −0.519 −108.496 −4.303 1.00 204.21 ATOM 1355 N THR D 20 2.142 −105.524 −2.331 1.00 192.45 ATOM 1356 CA THR D 20 3.373 −104.732 −2.196 1.00 189.49 ATOM 1357 C THR D 20 4.629 −105.599 −1.956 1.00 192.59 ATOM 1358 O THR D 20 4.642 −106.452 −1.077 1.00 194.63 ATOM 1359 CB THR D 20 3.195 −103.573 −1.190 1.00 194.36 ATOM 1360 OG1 THR D 20 2.348 −102.602 −1.803 1.00 186.15 ATOM 1361 CG2 THR D 20 4.511 −102.882 −0.835 1.00 190.19 ATOM 1362 N MET D 21 5.682 −105.360 −2.715 1.00 185.25 ATOM 1363 CA MET D 21 6.928 −106.087 −2.554 1.00 185.08 ATOM 1364 C MET D 21 8.043 −105.084 −2.406 1.00 190.70 ATOM 1365 O MET D 21 7.937 −104.013 −2.991 1.00 190.70 ATOM 1366 CB MET D 21 7.164 −107.005 −3.746 1.00 186.69 ATOM 1367 CG MET D 21 7.257 −106.295 −5.056 1.00 188.19 ATOM 1368 SD MET D 21 6.773 −107.331 −6.421 1.00 193.27 ATOM 1369 CE MET D 21 4.963 −106.726 −6.632 1.00 190.78 ATOM 1370 N SER D 22 9.099 −105.394 −1.633 1.00 187.95 ATOM 1371 CA SER D 22 10.175 −104.430 −1.396 1.00 186.81 ATOM 1372 C SER D 22 11.527 −104.766 −1.992 1.00 190.81 ATOM 1373 O SER D 22 11.757 −105.908 −2.385 1.00 189.78 ATOM 1374 CB SER D 22 10.305 −104.137 0.087 1.00 191.56 ATOM 1375 OG SER D 22 10.572 −105.357 0.746 1.00 200.62 ATOM 1376 N CYS D 23 12.419 −103.750 −2.058 1.00 188.69 ATOM 1377 CA CYS D 23 13.774 −103.814 −2.629 1.00 189.47 ATOM 1378 C CYS D 23 14.703 −102.985 −1.777 1.00 191.36 ATOM 1379 O CYS D 23 14.318 −101.912 −1.326 1.00 191.16 ATOM 1380 CB CYS D 23 13.757 −103.322 −4.083 1.00 189.38 ATOM 1381 SG CYS D 23 15.388 −103.179 −4.884 1.00 194.58 ATOM 1382 N LYS D 24 15.918 −103.457 −1.553 1.00 187.81 ATOM 1383 CA LYS D 24 16.888 −102.712 −0.748 1.00 189.71 ATOM 1384 C LYS D 24 18.253 −102.685 −1.403 1.00 195.48 ATOM 1385 O LYS D 24 18.715 −103.713 −1.895 1.00 197.67 ATOM 1386 CB LYS D 24 16.979 −103.258 0.687 1.00 195.01 ATOM 1387 CG LYS D 24 17.570 −102.257 1.712 1.00 205.65 ATOM 1388 CD LYS D 24 18.081 −102.919 3.038 1.00 215.49 ATOM 1389 CE LYS D 24 19.106 −104.061 2.949 1.00 214.97 ATOM 1390 NZ LYS D 24 19.635 −104.476 4.284 1.00 211.92 ATOM 1391 N SER D 25 18.921 −101.531 −1.361 1.00 190.72 ATOM 1392 CA SER D 25 20.244 −101.366 −1.947 1.00 191.20 ATOM 1393 C SER D 25 21.232 −101.034 −0.855 1.00 198.70 ATOM 1394 O SER D 25 20.907 −100.290 0.072 1.00 198.77 ATOM 1395 CB SER D 25 20.201 −100.251 −2.983 1.00 190.75 ATOM 1396 OG SER D 25 21.308 −100.165 −3.855 1.00 195.49 ATOM 1397 N SER D 26 22.434 −101.594 −0.958 1.00 198.42 ATOM 1398 CA SER D 26 23.526 −101.381 −0.007 1.00 202.70 ATOM 1399 C SER D 26 24.050 −99.942 −0.009 1.00 208.22 ATOM 1400 O SER D 26 24.785 −99.561 0.903 1.00 211.59 ATOM 1401 CB SER D 26 24.668 −102.336 −0.319 1.00 209.79 ATOM 1402 OG SER D 26 24.999 −102.237 −1.694 1.00 217.86 ATOM 1403 N GLN D 27 23.666 −99.147 −1.016 1.00 202.53 ATOM 1404 CA GLN D 27 24.098 −97.757 −1.173 1.00 203.52 ATOM 1405 C GLN D 27 22.932 −96.910 −1.653 1.00 203.00 ATOM 1406 O GLN D 27 22.038 −97.464 −2.273 1.00 199.36 ATOM 1407 CB GLN D 27 25.234 −97.744 −2.200 1.00 207.14 ATOM 1408 CG GLN D 27 25.966 −96.427 −2.441 1.00 224.70 ATOM 1409 CD GLN D 27 26.935 −96.597 −3.609 1.00 237.11 ATOM 1410 OE1 GLN D 27 26.823 −95.919 −4.641 1.00 232.36 ATOM 1411 NE2 GLN D 27 27.819 −97.609 −3.542 1.00 219.82 ATOM 1412 N SER D 28 22.928 −95.580 −1.383 1.00 201.25 ATOM 1413 CA SER D 28 21.837 −94.679 −1.836 1.00 198.77 ATOM 1414 C SER D 28 21.831 −94.482 −3.328 1.00 202.25 ATOM 1415 O SER D 28 22.873 −94.224 −3.936 1.00 203.42 ATOM 1416 CB SER D 28 21.867 −93.310 −1.162 1.00 204.36 ATOM 1417 OG SER D 28 20.909 −92.436 −1.751 1.00 207.36 ATOM 1418 N LEU D 29 20.635 −94.570 −3.907 1.00 196.93 ATOM 1419 CA LEU D 29 20.465 −94.481 −5.349 1.00 195.59 ATOM 1420 C LEU D 29 19.856 −93.148 −5.744 1.00 198.59 ATOM 1421 O LEU D 29 19.494 −92.936 −6.907 1.00 197.03 ATOM 1422 CB LEU D 29 19.610 −95.668 −5.867 1.00 193.26 ATOM 1423 CG LEU D 29 19.984 −97.090 −5.417 1.00 198.16 ATOM 1424 CD1 LEU D 29 19.044 −98.096 −6.021 1.00 195.29 ATOM 1425 CD2 LEU D 29 21.423 −97.418 −5.765 1.00 202.98 ATOM 1426 N LEU D 30 19.770 −92.231 −4.784 1.00 195.19 ATOM 1427 CA LEU D 30 19.185 −90.929 −5.059 1.00 192.56 ATOM 1428 C LEU D 30 20.207 −89.989 −5.657 1.00 195.61 ATOM 1429 O LEU D 30 21.179 −89.623 −4.992 1.00 200.33 ATOM 1430 CB LEU D 30 18.514 −90.377 −3.804 1.00 192.47 ATOM 1431 CG LEU D 30 17.944 −88.975 −3.840 1.00 195.85 ATOM 1432 CD1 LEU D 30 16.984 −88.771 −4.996 1.00 192.09 ATOM 1433 CD2 LEU D 30 17.222 −88.704 −2.558 1.00 200.02 ATOM 1434 N TYR D 31 19.974 −89.628 −6.942 1.00 185.23 ATOM 1435 CA TYR D 31 20.817 −88.751 −7.736 1.00 183.96 ATOM 1436 C TYR D 31 20.714 −87.327 −7.229 1.00 189.61 ATOM 1437 O TYR D 31 19.644 −86.728 −7.319 1.00 187.01 ATOM 1438 CB TYR D 31 20.443 −88.796 −9.224 1.00 179.36 ATOM 1439 CG TYR D 31 21.546 −88.318 −10.128 1.00 178.22 ATOM 1440 CD1 TYR D 31 22.804 −88.022 −9.625 1.00 182.83 ATOM 1441 CD2 TYR D 31 21.358 −88.232 −11.493 1.00 177.09 ATOM 1442 CE1 TYR D 31 23.838 −87.645 −10.453 1.00 184.40 ATOM 1443 CE2 TYR D 31 22.398 −87.882 −12.338 1.00 180.80 ATOM 1444 CZ TYR D 31 23.640 −87.589 −11.812 1.00 189.00 ATOM 1445 OH TYR D 31 24.689 −87.260 −12.627 1.00 192.03 ATOM 1446 N SER D 32 21.834 −86.784 −6.711 1.00 189.26 ATOM 1447 CA SER D 32 21.917 −85.434 −6.179 1.00 190.19 ATOM 1448 C SER D 32 21.390 −84.373 −7.164 1.00 193.89 ATOM 1449 O SER D 32 20.301 −83.825 −6.943 1.00 191.71 ATOM 1450 CB SER D 32 23.340 −85.133 −5.729 1.00 197.42 ATOM 1451 OG SER D 32 24.238 −85.232 −6.820 1.00 206.93 ATOM 1452 N SER D 33 22.117 −84.124 −8.272 1.00 191.54 ATOM 1453 CA SER D 33 21.699 −83.132 −9.257 1.00 189.53 ATOM 1454 C SER D 33 20.601 −83.676 −10.114 1.00 189.65 ATOM 1455 O SER D 33 20.809 −83.876 −11.310 1.00 189.36 ATOM 1456 CB SER D 33 22.871 −82.714 −10.130 1.00 195.21 ATOM 1457 OG SER D 33 23.407 −83.839 −10.809 1.00 200.36 ATOM 1458 N ASN D 34 19.427 −83.909 −9.519 1.00 184.28 ATOM 1459 CA ASN D 34 18.302 −84.466 −10.238 1.00 182.47 ATOM 1460 C ASN D 34 17.129 −84.649 −9.314 1.00 190.01 ATOM 1461 O ASN D 34 15.980 −84.357 −9.689 1.00 185.92 ATOM 1462 CB ASN D 34 18.689 −85.842 −10.820 1.00 184.45 ATOM 1463 CG ASN D 34 17.679 −86.389 −11.788 1.00 209.29 ATOM 1464 OD1 ASN D 34 17.739 −87.552 −12.177 1.00 212.67 ATOM 1465 ND2 ASN D 34 16.714 −85.576 −12.200 1.00 193.35 ATOM 1466 N GLN D 35 17.424 −85.216 −8.122 1.00 193.14 ATOM 1467 CA GLN D 35 16.456 −85.569 −7.075 1.00 193.23 ATOM 1468 C GLN D 35 15.587 −86.779 −7.469 1.00 193.97 ATOM 1469 O GLN D 35 14.464 −86.934 −6.982 1.00 191.59 ATOM 1470 CB GLN D 35 15.629 −84.350 −6.627 1.00 194.47 ATOM 1471 CG GLN D 35 16.472 −83.204 −6.051 1.00 205.79 ATOM 1472 CD GLN D 35 17.046 −83.496 −4.683 1.00 210.28 ATOM 1473 OE1 GLN D 35 17.564 −84.582 −4.407 1.00 197.15 ATOM 1474 NE2 GLN D 35 17.101 −82.474 −3.839 1.00 204.58 ATOM 1475 N LYS D 36 16.160 −87.658 −8.319 1.00 190.17 ATOM 1476 CA LYS D 36 15.549 −88.898 −8.805 1.00 188.31 ATOM 1477 C LYS D 36 16.351 −90.114 −8.317 1.00 193.72 ATOM 1478 O LYS D 36 17.557 −90.027 −8.072 1.00 196.83 ATOM 1479 CB LYS D 36 15.410 −88.909 −10.333 1.00 189.11 ATOM 1480 CG LYS D 36 14.661 −87.696 −10.891 1.00 193.77 ATOM 1481 CD LYS D 36 14.124 −87.942 −12.286 1.00 195.32 ATOM 1482 CE LYS D 36 12.627 −87.784 −12.338 1.00 197.19 ATOM 1483 NZ LYS D 36 12.114 −88.014 −13.701 1.00 209.34 ATOM 1484 N ASN D 37 15.668 −91.223 −8.132 1.00 186.47 ATOM 1485 CA ASN D 37 16.288 −92.425 −7.624 1.00 186.10 ATOM 1486 C ASN D 37 16.615 −93.289 −8.807 1.00 186.85 ATOM 1487 O ASN D 37 15.730 −93.562 −9.588 1.00 183.99 ATOM 1488 CB ASN D 37 15.288 −93.113 −6.708 1.00 187.62 ATOM 1489 CG ASN D 37 15.189 −92.492 −5.334 1.00 210.54 ATOM 1490 OD1 ASN D 37 16.019 −92.779 −4.467 1.00 194.98 ATOM 1491 ND2 ASN D 37 14.172 −91.640 −5.099 1.00 204.81 ATOM 1492 N PHE D 38 17.856 −93.719 −8.973 1.00 185.33 ATOM 1493 CA PHE D 38 18.239 −94.574 −10.103 1.00 185.27 ATOM 1494 C PHE D 38 17.852 −96.045 −9.932 1.00 192.74 ATOM 1495 O PHE D 38 18.714 −96.917 −9.899 1.00 193.92 ATOM 1496 CB PHE D 38 19.709 −94.345 −10.470 1.00 188.58 ATOM 1497 CG PHE D 38 19.821 −93.123 −11.347 1.00 189.12 ATOM 1498 CD2 PHE D 38 20.663 −93.120 −12.440 1.00 192.05 ATOM 1499 CD1 PHE D 38 18.890 −92.083 −11.247 1.00 190.10 ATOM 1500 CE2 PHE D 38 20.726 −92.022 −13.295 1.00 195.19 ATOM 1501 CE1 PHE D 38 18.905 −91.014 −12.139 1.00 190.91 ATOM 1502 CZ PHE D 38 19.821 −90.995 −13.163 1.00 191.75 ATOM 1503 N LEU D 39 16.550 −96.316 −9.816 1.00 190.07 ATOM 1504 CA LEU D 39 16.062 −97.674 −9.626 1.00 190.88 ATOM 1505 C LEU D 39 14.930 −97.972 −10.578 1.00 195.37 ATOM 1506 O LEU D 39 14.160 −97.065 −10.923 1.00 196.60 ATOM 1507 CB LEU D 39 15.656 −97.890 −8.158 1.00 191.08 ATOM 1508 CG LEU D 39 15.019 −99.210 −7.696 1.00 195.68 ATOM 1509 CD1 LEU D 39 15.847 −100.453 −7.842 1.00 196.91 ATOM 1510 CD2 LEU D 39 13.537 −99.261 −7.865 1.00 197.21 ATOM 1511 N ALA D 40 14.831 −99.241 −11.006 1.00 188.96 ATOM 1512 CA ALA D 40 13.790 −99.664 −11.922 1.00 186.21 ATOM 1513 C ALA D 40 13.166 −100.919 −11.476 1.00 188.36 ATOM 1514 O ALA D 40 13.786 −101.661 −10.727 1.00 189.80 ATOM 1515 CB ALA D 40 14.363 −99.849 −13.311 1.00 187.42 ATOM 1516 N TRP D 41 11.944 −101.169 −11.946 1.00 183.45 ATOM 1517 CA TRP D 41 11.190 −102.385 −11.691 1.00 184.49 ATOM 1518 C TRP D 41 10.837 −103.067 −12.981 1.00 187.31 ATOM 1519 O TRP D 41 10.413 −102.427 −13.937 1.00 188.26 ATOM 1520 CB TRP D 41 9.919 −102.093 −10.960 1.00 183.88 ATOM 1521 CG TRP D 41 10.169 −101.797 −9.529 1.00 186.39 ATOM 1522 CD1 TRP D 41 10.266 −100.562 −8.969 1.00 189.18 ATOM 1523 CD2 TRP D 41 10.392 −102.749 −8.457 1.00 187.73 ATOM 1524 NE1 TRP D 41 10.465 −100.674 −7.607 1.00 190.36 ATOM 1525 CE2 TRP D 41 10.559 −102.006 −7.270 1.00 192.78 ATOM 1526 CE3 TRP D 41 10.418 −104.155 −8.375 1.00 189.82 ATOM 1527 CZ2 TRP D 41 10.761 −102.622 −6.022 1.00 193.13 ATOM 1528 CZ3 TRP D 41 10.593 −104.760 −7.134 1.00 192.09 ATOM 1529 CH2 TRP D 41 10.757 −104.001 −5.979 1.00 192.98 ATOM 1530 N TYR D 42 11.016 −104.366 −13.020 1.00 181.80 ATOM 1531 CA TYR D 42 10.707 −105.155 −14.195 1.00 180.50 ATOM 1532 C TYR D 42 9.705 −106.215 −13.795 1.00 184.45 ATOM 1533 O TYR D 42 9.661 −106.629 −12.623 1.00 186.48 ATOM 1534 CB TYR D 42 11.973 −105.818 −14.764 1.00 180.95 ATOM 1535 CG TYR D 42 12.925 −104.867 −15.436 1.00 180.26 ATOM 1536 CD2 TYR D 42 12.943 −104.736 −16.813 1.00 181.92 ATOM 1537 CD1 TYR D 42 13.851 −104.139 −14.697 1.00 181.56 ATOM 1538 CE2 TYR D 42 13.840 −103.882 −17.443 1.00 183.61 ATOM 1539 CE1 TYR D 42 14.733 −103.259 −15.310 1.00 184.24 ATOM 1540 CZ TYR D 42 14.730 −103.137 −16.685 1.00 193.71 ATOM 1541 OH TYR D 42 15.596 −102.248 −17.271 1.00 197.14 ATOM 1542 N GLN D 43 8.885 −106.640 −14.767 1.00 177.47 ATOM 1543 CA GLN D 43 7.921 −107.716 −14.589 1.00 176.61 ATOM 1544 C GLN D 43 8.240 −108.761 −15.628 1.00 184.12 ATOM 1545 O GLN D 43 8.422 −108.406 −16.800 1.00 183.39 ATOM 1546 CB GLN D 43 6.503 −107.238 −14.768 1.00 176.04 ATOM 1547 CG GLN D 43 5.525 −108.365 −14.844 1.00 158.91 ATOM 1548 CD GLN D 43 4.384 −108.045 −15.754 1.00 182.31 ATOM 1549 OE1 GLN D 43 3.227 −107.999 −15.335 1.00 182.46 ATOM 1550 NE2 GLN D 43 4.687 −108.013 −17.060 1.00 169.98 ATOM 1551 N GLN D 44 8.346 −110.046 −15.197 1.00 183.45 ATOM 1552 CA GLN D 44 8.643 −111.156 −16.097 1.00 184.72 ATOM 1553 C GLN D 44 7.600 −112.226 −15.966 1.00 190.81 ATOM 1554 O GLN D 44 7.619 −112.960 −14.982 1.00 191.68 ATOM 1555 CB GLN D 44 10.058 −111.721 −15.893 1.00 185.24 ATOM 1556 CG GLN D 44 10.364 −112.825 −16.882 1.00 195.88 ATOM 1557 CD GLN D 44 11.762 −113.364 −16.797 1.00 224.89 ATOM 1558 OE1 GLN D 44 12.291 −113.660 −15.721 1.00 221.88 ATOM 1559 NE2 GLN D 44 12.370 −113.578 −17.954 1.00 222.77 ATOM 1560 N LYS D 45 6.687 −112.313 −16.950 1.00 187.58 ATOM 1561 CA LYS D 45 5.672 −113.358 −16.967 1.00 189.76 ATOM 1562 C LYS D 45 6.398 −114.637 −17.389 1.00 196.87 ATOM 1563 O LYS D 45 7.409 −114.542 −18.115 1.00 197.53 ATOM 1564 CB LYS D 45 4.537 −113.030 −17.916 1.00 192.28 ATOM 1565 CG LYS D 45 3.884 −111.724 −17.557 1.00 187.20 ATOM 1566 CD LYS D 45 2.637 −111.444 −18.364 1.00 190.01 ATOM 1567 CE LYS D 45 2.132 −110.050 −18.078 1.00 188.70 ATOM 1568 NZ LYS D 45 0.802 −109.799 −18.689 1.00 194.46 ATOM 1569 N PRO D 46 5.970 −115.831 −16.897 1.00 192.55 ATOM 1570 CA PRO D 46 6.750 −117.029 −17.158 1.00 192.53 ATOM 1571 C PRO D 46 6.814 −117.376 −18.624 1.00 197.88 ATOM 1572 O PRO D 46 5.821 −117.254 −19.329 1.00 198.74 ATOM 1573 CB PRO D 46 6.058 −118.066 −16.287 1.00 196.19 ATOM 1574 CG PRO D 46 5.409 −117.278 −15.200 1.00 198.93 ATOM 1575 CD PRO D 46 4.855 −116.142 −15.979 1.00 194.21 ATOM 1576 N GLY D 47 8.016 −117.694 −19.082 1.00 195.71 ATOM 1577 CA GLY D 47 8.267 −118.078 −20.470 1.00 198.62 ATOM 1578 C GLY D 47 8.411 −116.902 −21.407 1.00 201.22 ATOM 1579 O GLY D 47 8.686 −117.071 −22.603 1.00 202.74 ATOM 1580 N GLN D 48 8.226 −115.707 −20.866 1.00 194.79 ATOM 1581 CA GLN D 48 8.359 −114.502 −21.656 1.00 194.24 ATOM 1582 C GLN D 48 9.596 −113.738 −21.245 1.00 197.72 ATOM 1583 O GLN D 48 10.218 −114.049 −20.233 1.00 196.48 ATOM 1584 CB GLN D 48 7.112 −113.619 −21.498 1.00 194.64 ATOM 1585 CG GLN D 48 5.900 −114.116 −22.276 1.00 202.71 ATOM 1586 CD GLN D 48 4.734 −113.183 −22.150 1.00 220.40 ATOM 1587 OE1 GLN D 48 4.871 −111.970 −22.322 1.00 222.06 ATOM 1588 NE2 GLN D 48 3.557 −113.727 −21.857 1.00 206.68 ATOM 1589 N SER D 49 9.953 −112.725 −22.027 1.00 194.86 ATOM 1590 CA SER D 49 11.063 −111.870 −21.675 1.00 192.73 ATOM 1591 C SER D 49 10.567 −110.819 −20.674 1.00 195.32 ATOM 1592 O SER D 49 9.372 −110.502 −20.634 1.00 194.16 ATOM 1593 CB SER D 49 11.650 −111.211 −22.912 1.00 196.02 ATOM 1594 OG SER D 49 12.543 −112.137 −23.498 1.00 208.08 ATOM 1595 N PRO D 50 11.471 −110.278 −19.843 1.00 191.78 ATOM 1596 CA PRO D 50 11.070 −109.248 −18.887 1.00 189.02 ATOM 1597 C PRO D 50 10.615 −107.962 −19.571 1.00 190.86 ATOM 1598 O PRO D 50 10.927 −107.708 −20.743 1.00 192.21 ATOM 1599 CB PRO D 50 12.346 −109.018 −18.074 1.00 190.22 ATOM 1600 CG PRO D 50 13.135 −110.218 −18.275 1.00 197.48 ATOM 1601 CD PRO D 50 12.908 −110.550 −19.710 1.00 194.92 ATOM 1602 N LYS D 51 9.865 −107.152 −18.827 1.00 183.40 ATOM 1603 CA LYS D 51 9.313 −105.921 −19.348 1.00 181.41 ATOM 1604 C LYS D 51 9.588 −104.776 −18.386 1.00 182.97 ATOM 1605 O LYS D 51 9.421 −104.962 −17.177 1.00 183.82 ATOM 1606 CB LYS D 51 7.802 −106.112 −19.573 1.00 183.96 ATOM 1607 CG LYS D 51 7.059 −104.848 −19.981 1.00 198.44 ATOM 1608 CD LYS D 51 5.537 −105.025 −19.942 1.00 207.89 ATOM 1609 CE LYS D 51 4.785 −103.726 −20.195 1.00 200.67 ATOM 1610 NZ LYS D 51 3.297 −103.848 −20.021 1.00 187.98 ATOM 1611 N LEU D 52 10.001 −103.595 −18.906 1.00 175.19 ATOM 1612 CA LEU D 52 10.227 −102.444 −18.037 1.00 170.84 ATOM 1613 C LEU D 52 8.894 −101.864 −17.608 1.00 173.17 ATOM 1614 O LEU D 52 8.038 −101.591 −18.439 1.00 173.34 ATOM 1615 CB LEU D 52 11.079 −101.375 −18.719 1.00 169.58 ATOM 1616 CG LEU D 52 11.354 −100.126 −17.876 1.00 170.91 ATOM 1617 CD1 LEU D 52 12.123 −100.472 −16.642 1.00 169.69 ATOM 1618 CD2 LEU D 52 12.105 −99.092 −18.673 1.00 174.06 ATOM 1619 N LEU D 53 8.708 −101.699 −16.322 1.00 169.53 ATOM 1620 CA LEU D 53 7.467 −101.131 −15.830 1.00 170.08 ATOM 1621 C LEU D 53 7.708 −99.702 −15.294 1.00 174.31 ATOM 1622 O LEU D 53 6.959 −98.751 −15.592 1.00 174.79 ATOM 1623 CB LEU D 53 6.923 −101.981 −14.674 1.00 170.94 ATOM 1624 CG LEU D 53 6.491 −103.368 −14.923 1.00 178.24 ATOM 1625 CD1 LEU D 53 6.296 −104.078 −13.604 1.00 179.59 ATOM 1626 CD2 LEU D 53 5.215 −103.378 −15.721 1.00 183.03 ATOM 1627 N ILE D 54 8.719 −99.580 −14.432 1.00 167.68 ATOM 1628 CA ILE D 54 8.971 −98.347 −13.752 1.00 164.55 ATOM 1629 C ILE D 54 10.417 −98.009 −13.695 1.00 173.06 ATOM 1630 O ILE D 54 11.238 −98.869 −13.415 1.00 175.53 ATOM 1631 CB ILE D 54 8.390 −98.470 −12.346 1.00 166.02 ATOM 1632 CG1 ILE D 54 6.881 −98.589 −12.395 1.00 165.36 ATOM 1633 CG2 ILE D 54 8.766 −97.266 −11.538 1.00 166.83 ATOM 1634 CD1 ILE D 54 6.275 −98.936 −11.109 1.00 168.49 ATOM 1635 N TYR D 55 10.721 −96.743 −13.905 1.00 171.69 ATOM 1636 CA TYR D 55 12.064 −96.213 −13.788 1.00 174.22 ATOM 1637 C TYR D 55 12.052 −94.961 −12.959 1.00 181.10 ATOM 1638 O TYR D 55 10.990 −94.391 −12.712 1.00 179.27 ATOM 1639 CB TYR D 55 12.733 −96.016 −15.137 1.00 177.05 ATOM 1640 CG TYR D 55 11.989 −95.146 −16.109 1.00 180.63 ATOM 1641 CD2 TYR D 55 12.411 −93.848 −16.372 1.00 182.07 ATOM 1642 CD1 TYR D 55 10.910 −95.641 −16.833 1.00 183.13 ATOM 1643 CE2 TYR D 55 11.735 −93.039 −17.291 1.00 182.80 ATOM 1644 CE1 TYR D 55 10.228 −94.845 −17.757 1.00 184.38 ATOM 1645 CZ TYR D 55 10.644 −93.543 −17.986 1.00 189.41 ATOM 1646 OH TYR D 55 9.968 −92.764 −18.897 1.00 187.27 ATOM 1647 N TRP D 56 13.213 −94.552 −12.479 1.00 182.07 ATOM 1648 CA TRP D 56 13.279 −93.416 −11.593 1.00 183.64 ATOM 1649 C TRP D 56 12.486 −93.692 −10.341 1.00 188.89 ATOM 1650 O TRP D 56 11.987 −92.759 −9.706 1.00 190.14 ATOM 1651 CB TRP D 56 12.885 −92.121 −12.297 1.00 182.29 ATOM 1652 CG TRP D 56 14.073 −91.571 −12.997 1.00 185.37 ATOM 1653 CD1 TRP D 56 15.360 −91.557 −12.537 1.00 190.33 ATOM 1654 CD2 TRP D 56 14.103 −90.985 −14.282 1.00 185.74 ATOM 1655 NE1 TRP D 56 16.188 −90.995 −13.465 1.00 191.25 ATOM 1656 CE2 TRP D 56 15.450 −90.665 −14.565 1.00 192.12 ATOM 1657 CE3 TRP D 56 13.117 −90.675 −15.227 1.00 186.47 ATOM 1658 CZ2 TRP D 56 15.825 −89.994 −15.728 1.00 193.13 ATOM 1659 CZ3 TRP D 56 13.501 −90.093 −16.420 1.00 189.44 ATOM 1660 CH2 TRP D 56 14.844 −89.771 −16.669 1.00 192.37 ATOM 1661 N ALA D 57 12.356 −95.000 −10.004 1.00 184.34 ATOM 1662 CA ALA D 57 11.611 −95.519 −8.870 1.00 184.25 ATOM 1663 C ALA D 57 10.110 −95.246 −8.937 1.00 186.13 ATOM 1664 O ALA D 57 9.374 −96.057 −8.389 1.00 187.32 ATOM 1665 CB ALA D 57 12.167 −94.981 −7.572 1.00 186.33 ATOM 1666 N SER D 58 9.635 −94.131 −9.562 1.00 178.39 ATOM 1667 CA SER D 58 8.207 −93.819 −9.613 1.00 175.61 ATOM 1668 C SER D 58 7.633 −93.545 −10.994 1.00 176.39 ATOM 1669 O SER D 58 6.416 −93.568 −11.126 1.00 174.82 ATOM 1670 CB SER D 58 7.878 −92.684 −8.654 1.00 178.29 ATOM 1671 OG SER D 58 8.085 −91.418 −9.263 1.00 187.42 ATOM 1672 N THR D 59 8.472 −93.263 −12.011 1.00 173.68 ATOM 1673 CA THR D 59 7.972 −92.995 −13.366 1.00 174.53 ATOM 1674 C THR D 59 7.487 −94.255 −14.062 1.00 183.41 ATOM 1675 O THR D 59 8.267 −95.168 −14.320 1.00 184.87 ATOM 1676 CB THR D 59 9.006 −92.298 −14.238 1.00 183.90 ATOM 1677 OG1 THR D 59 9.411 −91.079 −13.604 1.00 184.39 ATOM 1678 CG2 THR D 59 8.484 −92.043 −15.658 1.00 183.39 ATOM 1679 N ARG D 60 6.211 −94.277 −14.413 1.00 181.92 ATOM 1680 CA ARG D 60 5.577 −95.397 −15.097 1.00 183.19 ATOM 1681 C ARG D 60 5.912 −95.346 −16.580 1.00 187.22 ATOM 1682 O ARG D 60 5.802 −94.288 −17.205 1.00 185.93 ATOM 1683 CB ARG D 60 4.065 −95.270 −14.924 1.00 185.11 ATOM 1684 CG ARG D 60 3.299 −96.565 −15.017 1.00 198.01 ATOM 1685 CD ARG D 60 1.979 −96.402 −14.289 1.00 202.10 ATOM 1686 NE ARG D 60 2.180 −95.673 −13.026 1.00 210.51 ATOM 1687 CZ ARG D 60 1.250 −95.458 −12.098 1.00 221.41 ATOM 1688 NH1 ARG D 60 0.027 −95.935 −12.251 1.00 214.54 ATOM 1689 NH2 ARG D 60 1.551 −94.793 −10.991 1.00 196.32 ATOM 1690 N GLU D 61 6.301 −96.490 −17.146 1.00 185.56 ATOM 1691 CA GLU D 61 6.623 −96.590 −18.564 1.00 186.94 ATOM 1692 C GLU D 61 5.345 −96.447 −19.367 1.00 192.95 ATOM 1693 O GLU D 61 4.284 −96.841 −18.891 1.00 193.89 ATOM 1694 CB GLU D 61 7.297 −97.945 −18.852 1.00 189.90 ATOM 1695 CG GLU D 61 7.662 −98.218 −20.307 1.00 203.82 ATOM 1696 CD GLU D 61 8.649 −97.249 −20.915 1.00 230.96 ATOM 1697 OE1 GLU D 61 9.687 −96.963 −20.275 1.00 242.81 ATOM 1698 OE2 GLU D 61 8.400 −96.815 −22.061 1.00 221.22 ATOM 1699 N SER D 62 5.431 −95.892 −20.573 1.00 190.41 ATOM 1700 CA SER D 62 4.235 −95.776 −21.389 1.00 191.83 ATOM 1701 C SER D 62 3.711 −97.148 −21.777 1.00 194.60 ATOM 1702 O SER D 62 4.492 −98.036 −22.098 1.00 193.38 ATOM 1703 CB SER D 62 4.481 −94.925 −22.621 1.00 198.54 ATOM 1704 OG SER D 62 3.212 −94.498 −23.092 1.00 212.77 ATOM 1705 N GLY D 63 2.400 −97.304 −21.682 1.00 192.56 ATOM 1706 CA GLY D 63 1.708 −98.552 −21.958 1.00 195.44 ATOM 1707 C GLY D 63 1.649 −99.451 −20.743 1.00 199.81 ATOM 1708 O GLY D 63 1.404 −100.657 −20.876 1.00 202.47 ATOM 1709 N VAL D 64 1.910 −98.872 −19.555 1.00 192.98 ATOM 1710 CA VAL D 64 1.899 −99.603 −18.298 1.00 192.43 ATOM 1711 C VAL D 64 0.658 −99.205 −17.526 1.00 201.14 ATOM 1712 O VAL D 64 0.464 −98.023 −17.196 1.00 199.33 ATOM 1713 CB VAL D 64 3.222 −99.513 −17.475 1.00 191.77 ATOM 1714 CG1 VAL D 64 3.066 −100.060 −16.067 1.00 190.89 ATOM 1715 CG2 VAL D 64 4.346 −100.244 −18.171 1.00 191.38 ATOM 1716 N PRO D 65 −0.187 −100.216 −17.232 1.00 203.43 ATOM 1717 CA PRO D 65 −1.408 −99.961 −16.457 1.00 205.77 ATOM 1718 C PRO D 65 −1.163 −99.136 −15.199 1.00 208.08 ATOM 1719 O PRO D 65 −0.107 −99.252 −14.565 1.00 206.69 ATOM 1720 CB PRO D 65 −1.881 −101.374 −16.100 1.00 210.71 ATOM 1721 CG PRO D 65 −1.401 −102.213 −17.233 1.00 215.95 ATOM 1722 CD PRO D 65 −0.049 −101.654 −17.552 1.00 207.75 ATOM 1723 N ASP D 66 −2.142 −98.314 −14.831 1.00 203.72 ATOM 1724 CA ASP D 66 −2.040 −97.491 −13.640 1.00 201.67 ATOM 1725 C ASP D 66 −2.024 −98.341 −12.374 1.00 202.63 ATOM 1726 O ASP D 66 −1.806 −97.836 −11.277 1.00 200.56 ATOM 1727 CB ASP D 66 −3.184 −96.473 −13.612 1.00 205.67 ATOM 1728 CG ASP D 66 −3.390 −95.763 −14.935 1.00 221.39 ATOM 1729 OD1 ASP D 66 −2.382 −95.342 −15.547 1.00 219.88 ATOM 1730 OD2 ASP D 66 −4.555 −95.653 −15.373 1.00 232.60 ATOM 1731 N ARG D 67 −2.218 −99.636 −12.542 1.00 200.16 ATOM 1732 CA ARG D 67 −2.249 −100.610 −11.465 1.00 201.55 ATOM 1733 C ARG D 67 −0.911 −100.708 −10.764 1.00 200.30 ATOM 1734 O ARG D 67 −0.869 −100.986 −9.566 1.00 199.69 ATOM 1735 CB ARG D 67 −2.643 −101.992 −12.027 1.00 206.89 ATOM 1736 CG ARG D 67 −3.955 −102.002 −12.812 1.00 219.57 ATOM 1737 CD ARG D 67 −4.566 −103.387 −12.907 1.00 228.88 ATOM 1738 NE ARG D 67 −3.611 −104.405 −13.346 1.00 234.98 ATOM 1739 CZ ARG D 67 −3.447 −104.757 −14.612 1.00 251.02 ATOM 1740 NH1 ARG D 67 −4.163 −104.174 −15.568 1.00 247.70 ATOM 1741 NH2 ARG D 67 −2.542 −105.656 −14.944 1.00 226.98 ATOM 1742 N PHE D 68 0.170 −100.453 −11.507 1.00 194.12 ATOM 1743 CA PHE D 68 1.545 −100.551 −11.015 1.00 192.37 ATOM 1744 C PHE D 68 2.039 −99.219 −10.489 1.00 192.59 ATOM 1745 O PHE D 68 1.997 −98.229 −11.210 1.00 192.74 ATOM 1746 CB PHE D 68 2.445 −101.140 −12.109 1.00 193.96 ATOM 1747 CG PHE D 68 1.983 −102.514 −12.582 1.00 198.33 ATOM 1748 CD2 PHE D 68 2.585 −103.672 −12.102 1.00 201.09 ATOM 1749 CD1 PHE D 68 0.913 −102.646 −13.472 1.00 203.37 ATOM 1750 CE2 PHE D 68 2.131 −104.935 −12.501 1.00 206.41 ATOM 1751 CE1 PHE D 68 0.449 −103.911 −13.855 1.00 206.98 ATOM 1752 CZ PHE D 68 1.074 −105.048 −13.382 1.00 206.64 ATOM 1753 N THR D 69 2.458 −99.183 −9.218 1.00 185.83 ATOM 1754 CA THR D 69 2.849 −97.959 −8.515 1.00 182.81 ATOM 1755 C THR D 69 4.142 −98.137 −7.718 1.00 184.84 ATOM 1756 O THR D 69 4.167 −98.814 −6.674 1.00 185.13 ATOM 1757 CB THR D 69 1.660 −97.407 −7.660 1.00 185.26 ATOM 1758 OG1 THR D 69 0.812 −98.456 −7.136 1.00 179.57 ATOM 1759 CG2 THR D 69 0.766 −96.457 −8.467 1.00 182.32 ATOM 1760 N GLY D 70 5.179 −97.455 −8.173 1.00 179.49 ATOM 1761 CA GLY D 70 6.506 −97.521 −7.581 1.00 179.16 ATOM 1762 C GLY D 70 6.711 −96.437 −6.560 1.00 184.70 ATOM 1763 O GLY D 70 6.380 −95.271 −6.819 1.00 185.83 ATOM 1764 N SER D 71 7.294 −96.813 −5.412 1.00 180.30 ATOM 1765 CA SER D 71 7.521 −95.930 −4.264 1.00 178.95 ATOM 1766 C SER D 71 8.924 −96.155 −3.657 1.00 176.12 ATOM 1767 O SER D 71 9.622 −97.110 −4.027 1.00 174.41 ATOM 1768 CB SER D 71 6.417 −96.171 −3.220 1.00 185.24 ATOM 1769 OG SER D 71 5.606 −97.332 −3.449 1.00 191.46 ATOM 1770 N GLY D 72 9.305 −95.289 −2.729 1.00 170.35 ATOM 1771 CA GLY D 72 10.571 −95.412 −2.020 1.00 170.68 ATOM 1772 C GLY D 72 11.660 −94.487 −2.501 1.00 170.89 ATOM 1773 O GLY D 72 11.625 −94.034 −3.651 1.00 167.84 ATOM 1774 N SER D 73 12.660 −94.241 −1.617 1.00 167.43 ATOM 1775 CA SER D 73 13.757 −93.328 −1.908 1.00 166.67 ATOM 1776 C SER D 73 14.978 −93.690 −1.111 1.00 168.74 ATOM 1777 O SER D 73 14.857 −94.291 −0.035 1.00 165.24 ATOM 1778 CB SER D 73 13.337 −91.886 −1.624 1.00 171.60 ATOM 1779 OG SER D 73 14.204 −90.938 −2.224 1.00 181.40 ATOM 1780 N GLY D 74 16.135 −93.358 −1.690 1.00 169.50 ATOM 1781 CA GLY D 74 17.440 −93.627 −1.114 1.00 174.48 ATOM 1782 C GLY D 74 17.842 −95.078 −1.246 1.00 184.14 ATOM 1783 O GLY D 74 18.356 −95.469 −2.293 1.00 183.08 ATOM 1784 N THR D 75 17.621 −95.888 −0.185 1.00 185.46 ATOM 1785 CA THR D 75 18.002 −97.305 −0.161 1.00 186.96 ATOM 1786 C THR D 75 16.836 −98.278 −0.080 1.00 192.46 ATOM 1787 O THR D 75 17.062 −99.473 −0.225 1.00 191.52 ATOM 1788 CB THR D 75 18.981 −97.572 0.993 1.00 198.02 ATOM 1789 OG1 THR D 75 18.339 −97.329 2.247 1.00 199.48 ATOM 1790 CG2 THR D 75 20.239 −96.746 0.888 1.00 198.65 ATOM 1791 N ASP D 76 15.612 −97.799 0.195 1.00 191.12 ATOM 1792 CA ASP D 76 14.453 −98.673 0.391 1.00 190.88 ATOM 1793 C ASP D 76 13.360 −98.376 −0.585 1.00 189.06 ATOM 1794 O ASP D 76 12.939 −97.221 −0.698 1.00 187.77 ATOM 1795 CB ASP D 76 13.940 −98.587 1.843 1.00 196.37 ATOM 1796 CG ASP D 76 15.013 −98.565 2.931 1.00 217.24 ATOM 1797 OD1 ASP D 76 15.076 −97.558 3.684 1.00 219.21 ATOM 1798 OD2 ASP D 76 15.788 −99.558 3.034 1.00 228.14 ATOM 1799 N PHE D 77 12.913 −99.416 −1.305 1.00 183.27 ATOM 1800 CA PHE D 77 11.924 −99.300 −2.384 1.00 181.25 ATOM 1801 C PHE D 77 10.842 −100.332 −2.342 1.00 182.19 ATOM 1802 O PHE D 77 11.042 −101.397 −1.786 1.00 181.92 ATOM 1803 CB PHE D 77 12.617 −99.324 −3.766 1.00 182.29 ATOM 1804 CG PHE D 77 13.637 −98.235 −3.932 1.00 184.58 ATOM 1805 CD1 PHE D 77 14.969 −98.459 −3.612 1.00 190.09 ATOM 1806 CD2 PHE D 77 13.267 −96.983 −4.402 1.00 186.38 ATOM 1807 CE1 PHE D 77 15.913 −97.443 −3.720 1.00 192.50 ATOM 1808 CE2 PHE D 77 14.206 −95.954 −4.484 1.00 190.61 ATOM 1809 CZ PHE D 77 15.524 −96.182 −4.108 1.00 191.09 ATOM 1810 N THR D 78 9.692 −100.012 −2.932 1.00 177.56 ATOM 1811 CA THR D 78 8.548 −100.906 −2.986 1.00 178.90 ATOM 1812 C THR D 78 7.844 −100.821 −4.331 1.00 184.34 ATOM 1813 O THR D 78 7.777 −99.759 −4.958 1.00 183.53 ATOM 1814 CB THR D 78 7.504 −100.627 −1.877 1.00 188.40 ATOM 1815 OG1 THR D 78 6.836 −99.394 −2.135 1.00 192.49 ATOM 1816 CG2 THR D 78 8.079 −100.641 −0.480 1.00 187.10 ATOM 1817 N LEU D 79 7.292 −101.942 −4.759 1.00 182.10 ATOM 1818 CA LEU D 79 6.500 −102.000 −5.972 1.00 180.69 ATOM 1819 C LEU D 79 5.115 −102.409 −5.546 1.00 190.01 ATOM 1820 O LEU D 79 4.967 −103.361 −4.777 1.00 192.54 ATOM 1821 CB LEU D 79 7.046 −102.978 −7.010 1.00 179.15 ATOM 1822 CG LEU D 79 6.153 −103.104 −8.238 1.00 181.84 ATOM 1823 CD1 LEU D 79 6.053 −101.824 −8.970 1.00 179.61 ATOM 1824 CD2 LEU D 79 6.651 −104.123 −9.156 1.00 186.16 ATOM 1825 N THR D 80 4.106 −101.697 −6.034 1.00 186.79 ATOM 1826 CA THR D 80 2.743 −101.989 −5.679 1.00 188.77 ATOM 1827 C THR D 80 1.892 −102.273 −6.908 1.00 193.47 ATOM 1828 O THR D 80 1.973 −101.553 −7.905 1.00 191.42 ATOM 1829 CB THR D 80 2.184 −100.826 −4.846 1.00 195.92 ATOM 1830 OG1 THR D 80 3.007 −100.615 −3.703 1.00 195.43 ATOM 1831 CG2 THR D 80 0.747 −101.044 −4.425 1.00 196.44 ATOM 1832 N ILE D 81 1.052 −103.311 −6.809 1.00 192.77 ATOM 1833 CA ILE D 81 0.032 −103.634 −7.797 1.00 193.20 ATOM 1834 C ILE D 81 −1.331 −103.428 −7.173 1.00 200.67 ATOM 1835 O ILE D 81 −1.751 −104.204 −6.313 1.00 201.01 ATOM 1836 CB ILE D 81 0.152 −105.017 −8.401 1.00 196.53 ATOM 1837 CG1 ILE D 81 1.545 −105.177 −9.029 1.00 193.45 ATOM 1838 CG2 ILE D 81 −1.002 −105.216 −9.420 1.00 198.93 ATOM 1839 CD1 ILE D 81 1.940 −106.547 −9.327 1.00 196.84 ATOM 1840 N SER D 82 −1.986 −102.335 −7.590 1.00 199.40 ATOM 1841 CA SER D 82 −3.324 −101.937 −7.222 1.00 203.31 ATOM 1842 C SER D 82 −4.127 −102.884 −8.098 1.00 210.21 ATOM 1843 O SER D 82 −3.753 −103.163 −9.247 1.00 208.34 ATOM 1844 CB SER D 82 −3.576 −100.484 −7.626 1.00 206.99 ATOM 1845 OG SER D 82 −2.605 −99.594 −7.081 1.00 215.69 ATOM 1846 N SER D 83 −5.100 −103.517 −7.476 1.00 210.94 ATOM 1847 CA SER D 83 −5.990 −104.558 −7.996 1.00 214.12 ATOM 1848 C SER D 83 −5.351 −105.552 −8.948 1.00 214.79 ATOM 1849 O SER D 83 −5.291 −105.299 −10.147 1.00 212.61 ATOM 1850 CB SER D 83 −7.289 −103.979 −8.548 1.00 220.53 ATOM 1851 OG SER D 83 −7.943 −104.843 −9.467 1.00 231.50 ATOM 1852 N VAL D 84 −4.892 −106.684 −8.417 1.00 211.27 ATOM 1853 CA VAL D 84 −4.267 −107.749 −9.197 1.00 209.85 ATOM 1854 C VAL D 84 −5.289 −108.341 −10.195 1.00 214.07 ATOM 1855 O VAL D 84 −6.425 −108.646 −9.823 1.00 218.37 ATOM 1856 CB VAL D 84 −3.642 −108.833 −8.273 1.00 214.57 ATOM 1857 CG1 VAL D 84 −3.155 −110.027 −9.074 1.00 215.31 ATOM 1858 CG2 VAL D 84 −2.494 −108.270 −7.443 1.00 210.40 ATOM 1859 N LYS D 85 −4.882 −108.448 −11.466 1.00 205.27 ATOM 1860 CA LYS D 85 −5.696 −109.023 −12.514 1.00 206.16 ATOM 1861 C LYS D 85 −5.084 −110.331 −12.885 1.00 209.74 ATOM 1862 O LYS D 85 −3.893 −110.549 −12.658 1.00 205.61 ATOM 1863 CB LYS D 85 −5.791 −108.092 −13.720 1.00 204.13 ATOM 1864 CG LYS D 85 −6.994 −107.169 −13.609 1.00 188.93 ATOM 1865 CD LYS D 85 −6.871 −105.991 −14.516 1.00 193.08 ATOM 1866 CE LYS D 85 −7.774 −104.843 −14.103 1.00 206.34 ATOM 1867 NZ LYS D 85 −7.555 −103.596 −14.911 1.00 209.61 ATOM 1868 N ALA D 86 −5.921 −111.204 −13.450 1.00 210.66 ATOM 1869 CA ALA D 86 −5.631 −112.558 −13.894 1.00 212.08 ATOM 1870 C ALA D 86 −4.171 −112.752 −14.360 1.00 211.52 ATOM 1871 O ALA D 86 −3.395 −113.573 −13.813 1.00 209.68 ATOM 1872 CB ALA D 86 −6.632 −112.956 −14.995 1.00 216.81 ATOM 1873 N GLU D 87 −3.789 −111.936 −15.324 1.00 205.45 ATOM 1874 CA GLU D 87 −2.488 −112.114 −15.894 1.00 202.29 ATOM 1875 C GLU D 87 −1.367 −111.429 −15.250 1.00 202.93 ATOM 1876 O GLU D 87 −0.270 −111.456 −15.806 1.00 200.02 ATOM 1877 CB GLU D 87 −2.472 −111.997 −17.417 1.00 203.98 ATOM 1878 CG GLU D 87 −3.198 −110.822 −18.010 1.00 206.37 ATOM 1879 CD GLU D 87 −2.779 −110.681 −19.452 1.00 210.19 ATOM 1880 OE1 GLU D 87 −1.858 −109.874 −19.718 1.00 211.63 ATOM 1881 OE2 GLU D 87 −3.262 −111.483 −20.284 1.00 184.05 ATOM 1882 N ASP D 88 −1.573 −110.892 −14.046 1.00 200.66 ATOM 1883 CA ASP D 88 −0.477 −110.217 −13.353 1.00 197.72 ATOM 1884 C ASP D 88 0.558 −111.167 −12.749 1.00 204.14 ATOM 1885 O ASP D 88 1.615 −110.729 −12.269 1.00 200.68 ATOM 1886 CB ASP D 88 −0.970 −109.158 −12.376 1.00 198.54 ATOM 1887 CG ASP D 88 −1.752 −107.998 −13.001 1.00 206.72 ATOM 1888 OD1 ASP D 88 −1.605 −107.764 −14.220 1.00 205.23 ATOM 1889 OD2 ASP D 88 −2.470 −107.292 −12.252 1.00 212.88 ATOM 1890 N LEU D 89 0.283 −112.484 −12.856 1.00 205.96 ATOM 1891 CA LEU D 89 1.203 −113.548 −12.434 1.00 206.34 ATOM 1892 C LEU D 89 2.552 −113.308 −13.099 1.00 208.82 ATOM 1893 O LEU D 89 2.613 −113.160 −14.325 1.00 207.67 ATOM 1894 CB LEU D 89 0.686 −114.925 −12.906 1.00 209.73 ATOM 1895 CG LEU D 89 1.339 −116.220 −12.348 1.00 213.51 ATOM 1896 CD1 LEU D 89 0.812 −116.556 −11.000 1.00 215.07 ATOM 1897 CD2 LEU D 89 2.903 −116.335 −12.466 1.00 209.74 ATOM 1898 N ALA D 90 3.628 −113.297 −12.299 1.00 204.73 ATOM 1899 CA ALA D 90 4.975 −113.111 −12.804 1.00 202.90 ATOM 1900 C ALA D 90 5.995 −112.947 −11.676 1.00 206.56 ATOM 1901 O ALA D 90 5.634 −112.964 −10.498 1.00 206.82 ATOM 1902 CB ALA D 90 5.012 −111.897 −13.711 1.00 201.60 ATOM 1903 N VAL D 91 7.283 −112.814 −12.055 1.00 201.49 ATOM 1904 CA VAL D 91 8.410 −112.579 −11.143 1.00 198.71 ATOM 1905 C VAL D 91 8.779 −111.120 −11.324 1.00 198.81 ATOM 1906 O VAL D 91 8.942 −110.662 −12.459 1.00 198.17 ATOM 1907 CB VAL D 91 9.631 −113.478 −11.422 1.00 202.32 ATOM 1908 CG1 VAL D 91 10.739 −113.205 −10.419 1.00 200.40 ATOM 1909 CG2 VAL D 91 9.239 −114.946 −11.384 1.00 205.18 ATOM 1910 N TYR D 92 8.911 −110.392 −10.215 1.00 191.93 ATOM 1911 CA TYR D 92 9.237 −108.975 −10.248 1.00 187.56 ATOM 1912 C TYR D 92 10.666 −108.729 −9.774 1.00 192.96 ATOM 1913 O TYR D 92 11.112 −109.317 −8.787 1.00 194.80 ATOM 1914 CB TYR D 92 8.190 −108.196 −9.456 1.00 185.58 ATOM 1915 CG TYR D 92 6.789 −108.290 −10.057 1.00 185.71 ATOM 1916 CD2 TYR D 92 5.982 −109.418 −9.854 1.00 187.79 ATOM 1917 CD1 TYR D 92 6.322 −107.318 −10.927 1.00 186.38 ATOM 1918 CE2 TYR D 92 4.701 −109.510 −10.419 1.00 189.42 ATOM 1919 CE1 TYR D 92 5.034 −107.380 −11.465 1.00 187.75 ATOM 1920 CZ TYR D 92 4.222 −108.471 −11.207 1.00 194.58 ATOM 1921 OH TYR D 92 2.968 −108.515 −11.786 1.00 196.32 ATOM 1922 N TYR D 93 11.402 −107.908 −10.514 1.00 188.88 ATOM 1923 CA TYR D 93 12.790 −107.599 −10.174 1.00 189.71 ATOM 1924 C TYR D 93 13.010 −106.112 −10.046 1.00 192.90 ATOM 1925 O TYR D 93 12.288 −105.333 −10.654 1.00 193.36 ATOM 1926 CB TYR D 93 13.750 −108.118 −11.248 1.00 192.77 ATOM 1927 CG TYR D 93 13.688 −109.606 −11.492 1.00 198.17 ATOM 1928 CD2 TYR D 93 14.533 −110.481 −10.813 1.00 200.41 ATOM 1929 CD1 TYR D 93 12.824 −110.140 −12.442 1.00 201.67 ATOM 1930 CE2 TYR D 93 14.493 −111.856 −11.049 1.00 203.05 ATOM 1931 CE1 TYR D 93 12.791 −111.511 −12.704 1.00 206.17 ATOM 1932 CZ TYR D 93 13.628 −112.367 −12.008 1.00 213.37 ATOM 1933 OH TYR D 93 13.558 −113.719 −12.264 1.00 217.03 ATOM 1934 N CYS D 94 14.005 −105.715 −9.263 1.00 187.97 ATOM 1935 CA CYS D 94 14.379 −104.324 −9.147 1.00 186.24 ATOM 1936 C CYS D 94 15.782 −104.274 −9.620 1.00 183.58 ATOM 1937 O CYS D 94 16.537 −105.215 −9.392 1.00 181.58 ATOM 1938 CB CYS D 94 14.232 −103.775 −7.721 1.00 188.19 ATOM 1939 SG CYS D 94 15.336 −104.522 −6.456 1.00 194.79 ATOM 1940 N GLN D 95 16.124 −103.202 −10.303 1.00 178.44 ATOM 1941 CA GLN D 95 17.463 −102.998 −10.810 1.00 179.23 ATOM 1942 C GLN D 95 17.951 −101.614 −10.455 1.00 183.94 ATOM 1943 O GLN D 95 17.194 −100.657 −10.595 1.00 181.63 ATOM 1944 CB GLN D 95 17.491 −103.163 −12.327 1.00 179.69 ATOM 1945 CG GLN D 95 18.879 −102.956 −12.896 1.00 180.44 ATOM 1946 CD GLN D 95 18.854 −102.687 −14.356 1.00 200.87 ATOM 1947 OE1 GLN D 95 18.392 −101.647 −14.821 1.00 183.33 ATOM 1948 NE2 GLN D 95 19.400 −103.603 −15.105 1.00 215.32 ATOM 1949 N GLN D 96 19.210 −101.503 −10.022 1.00 183.00 ATOM 1950 CA GLN D 96 19.809 −100.209 −9.769 1.00 183.65 ATOM 1951 C GLN D 96 20.645 −99.867 −10.991 1.00 191.02 ATOM 1952 O GLN D 96 21.311 −100.742 −11.526 1.00 193.49 ATOM 1953 CB GLN D 96 20.644 −100.202 −8.472 1.00 186.66 ATOM 1954 CG GLN D 96 21.955 −100.972 −8.473 1.00 202.10 ATOM 1955 CD GLN D 96 23.108 −100.243 −9.144 1.00 224.37 ATOM 1956 OE1 GLN D 96 23.194 −99.010 −9.169 1.00 213.64 ATOM 1957 NE2 GLN D 96 24.009 −100.998 −9.741 1.00 227.63 ATOM 1958 N TYR D 97 20.596 −98.630 −11.456 1.00 187.39 ATOM 1959 CA TYR D 97 21.413 −98.236 −12.594 1.00 189.45 ATOM 1960 C TYR D 97 22.182 −96.969 −12.256 1.00 195.65 ATOM 1961 O TYR D 97 22.461 −96.129 −13.112 1.00 196.37 ATOM 1962 CB TYR D 97 20.574 −98.110 −13.868 1.00 189.29 ATOM 1963 CG TYR D 97 19.325 −97.259 −13.751 1.00 188.50 ATOM 1964 CD2 TYR D 97 19.285 −95.969 −14.271 1.00 189.72 ATOM 1965 CD1 TYR D 97 18.152 −97.779 −13.214 1.00 187.16 ATOM 1966 CE2 TYR D 97 18.128 −95.202 −14.213 1.00 188.12 ATOM 1967 CE1 TYR D 97 16.990 −97.024 −13.158 1.00 183.43 ATOM 1968 CZ TYR D 97 16.985 −95.736 −13.656 1.00 191.55 ATOM 1969 OH TYR D 97 15.853 −94.974 −13.622 1.00 191.58 ATOM 1970 N PHE D 98 22.553 −96.859 −10.985 1.00 193.06 ATOM 1971 CA PHE D 98 23.288 −95.729 −10.449 1.00 194.54 ATOM 1972 C PHE D 98 24.736 −95.873 −10.852 1.00 199.60 ATOM 1973 O PHE D 98 25.283 −95.021 −11.563 1.00 199.35 ATOM 1974 CB PHE D 98 23.138 −95.725 −8.924 1.00 196.79 ATOM 1975 CG PHE D 98 23.602 −94.450 −8.292 1.00 200.38 ATOM 1976 CD2 PHE D 98 22.779 −93.326 −8.272 1.00 200.51 ATOM 1977 CD1 PHE D 98 24.851 −94.373 −7.690 1.00 207.68 ATOM 1978 CE2 PHE D 98 23.217 −92.137 −7.697 1.00 205.47 ATOM 1979 CE1 PHE D 98 25.293 −93.182 −7.115 1.00 210.90 ATOM 1980 CZ PHE D 98 24.484 −92.065 −7.145 1.00 208.04 ATOM 1981 N ARG D 99 25.335 −96.985 −10.419 1.00 197.90 ATOM 1982 CA ARG D 99 26.691 −97.337 −10.765 1.00 202.02 ATOM 1983 C ARG D 99 26.708 −98.772 −11.257 1.00 203.73 ATOM 1984 O ARG D 99 26.411 −99.731 −10.518 1.00 201.16 ATOM 1985 CB ARG D 99 27.714 −96.997 −9.671 1.00 207.32 ATOM 1986 CG ARG D 99 29.083 −96.572 −10.260 1.00 219.16 ATOM 1987 CD ARG D 99 28.950 −95.521 −11.369 1.00 213.79 ATOM 1988 NE ARG D 99 29.938 −95.671 −12.444 1.00 207.97 ATOM 1989 CZ ARG D 99 29.693 −96.166 −13.658 1.00 202.38 ATOM 1990 NH1 ARG D 99 28.474 −96.614 −13.972 1.00 161.04 ATOM 1991 NH2 ARG D 99 30.663 −96.227 −14.564 1.00 194.17 ATOM 1992 N TYR D 100 26.952 −98.901 −12.573 1.00 200.41 ATOM 1993 CA TYR D 100 26.862 −100.171 −13.269 1.00 199.62 ATOM 1994 C TYR D 100 25.351 −100.478 −13.190 1.00 196.13 ATOM 1995 O TYR D 100 24.531 −99.578 −12.992 1.00 194.78 ATOM 1996 CB TYR D 100 27.658 −101.279 −12.538 1.00 203.81 ATOM 1997 CG TYR D 100 29.140 −101.030 −12.416 1.00 211.93 ATOM 1998 CD1 TYR D 100 30.009 −101.426 −13.415 1.00 218.30 ATOM 1999 CD2 TYR D 100 29.681 −100.441 −11.273 1.00 214.67 ATOM 2000 CE1 TYR D 100 31.385 −101.215 −13.306 1.00 226.00 ATOM 2001 CE2 TYR D 100 31.054 −100.196 −11.163 1.00 221.29 ATOM 2002 CZ TYR D 100 31.906 −100.594 −12.183 1.00 233.84 ATOM 2003 OH TYR D 100 33.267 −100.399 −12.096 1.00 241.18 ATOM 2004 N ARG D 101 24.980 −101.733 −13.312 1.00 187.76 ATOM 2005 CA ARG D 101 23.582 −102.115 −13.190 1.00 182.13 ATOM 2006 C ARG D 101 23.530 −103.432 −12.500 1.00 186.38 ATOM 2007 O ARG D 101 24.337 −104.270 −12.797 1.00 190.29 ATOM 2008 CB ARG D 101 22.876 −102.178 −14.546 1.00 179.52 ATOM 2009 CG ARG D 101 22.825 −100.851 −15.291 1.00 186.38 ATOM 2010 CD ARG D 101 21.875 −100.875 −16.449 1.00 195.88 ATOM 2011 NE ARG D 101 21.789 −99.563 −17.074 1.00 214.61 ATOM 2012 CZ ARG D 101 20.641 −98.972 −17.390 1.00 239.43 ATOM 2013 NH1 ARG D 101 19.489 −99.595 −17.182 1.00 233.84 ATOM 2014 NH2 ARG D 101 20.638 −97.766 −17.953 1.00 224.93 ATOM 2015 N THR D 102 22.697 −103.605 −11.499 1.00 180.66 ATOM 2016 CA THR D 102 22.627 −104.893 −10.789 1.00 181.37 ATOM 2017 C THR D 102 21.181 −105.213 −10.521 1.00 184.97 ATOM 2018 O THR D 102 20.426 −104.301 −10.177 1.00 184.42 ATOM 2019 CB THR D 102 23.426 −104.876 −9.460 1.00 188.22 ATOM 2020 OG1 THR D 102 22.903 −103.861 −8.622 1.00 186.90 ATOM 2021 CG2 THR D 102 24.932 −104.662 −9.642 1.00 188.81 ATOM 2022 N PHE D 103 20.785 −106.490 −10.657 1.00 181.86 ATOM 2023 CA PHE D 103 19.395 −106.882 −10.388 1.00 180.59 ATOM 2024 C PHE D 103 19.243 −107.488 −9.024 1.00 191.12 ATOM 2025 O PHE D 103 20.172 −108.145 −8.559 1.00 195.00 ATOM 2026 CB PHE D 103 18.908 −107.918 −11.400 1.00 181.68 ATOM 2027 CG PHE D 103 18.625 −107.369 −12.763 1.00 181.62 ATOM 2028 CD2 PHE D 103 19.619 −107.342 −13.737 1.00 184.31 ATOM 2029 CD1 PHE D 103 17.359 −106.889 −13.085 1.00 182.06 ATOM 2030 CE2 PHE D 103 19.356 −106.844 −15.010 1.00 186.35 ATOM 2031 CE1 PHE D 103 17.095 −106.389 −14.357 1.00 182.37 ATOM 2032 CZ PHE D 103 18.094 −106.388 −15.320 1.00 182.53 ATOM 2033 N GLY D 104 18.063 −107.333 −8.417 1.00 188.14 ATOM 2034 CA GLY D 104 17.759 −107.993 −7.154 1.00 189.56 ATOM 2035 C GLY D 104 17.440 −109.459 −7.444 1.00 195.67 ATOM 2036 O GLY D 104 17.351 −109.882 −8.614 1.00 194.85 ATOM 2037 N GLY D 105 17.244 −110.236 −6.387 1.00 193.90 ATOM 2038 CA GLY D 105 16.913 −111.651 −6.533 1.00 194.96 ATOM 2039 C GLY D 105 15.532 −111.950 −7.099 1.00 197.55 ATOM 2040 O GLY D 105 15.254 −113.084 −7.493 1.00 198.82 ATOM 2041 N GLY D 106 14.667 −110.943 −7.123 1.00 191.42 ATOM 2042 CA GLY D 106 13.300 −111.072 −7.602 1.00 190.05 ATOM 2043 C GLY D 106 12.310 −111.603 −6.588 1.00 194.19 ATOM 2044 O GLY D 106 12.677 −112.321 −5.645 1.00 193.29 ATOM 2045 N THR D 107 11.031 −111.244 −6.798 1.00 192.34 ATOM 2046 CA THR D 107 9.900 −111.717 −5.997 1.00 194.83 ATOM 2047 C THR D 107 8.846 −112.415 −6.869 1.00 202.67 ATOM 2048 O THR D 107 8.360 −111.821 −7.830 1.00 202.14 ATOM 2049 CB THR D 107 9.290 −110.667 −5.065 1.00 203.22 ATOM 2050 OG1 THR D 107 7.903 −110.441 −5.321 1.00 202.67 ATOM 2051 CG2 THR D 107 10.156 −109.442 −4.777 1.00 200.85 ATOM 2052 N LYS D 108 8.504 −113.671 −6.542 1.00 202.28 ATOM 2053 CA LYS D 108 7.532 −114.446 −7.315 1.00 203.84 ATOM 2054 C LYS D 108 6.094 −114.219 −6.822 1.00 210.93 ATOM 2055 O LYS D 108 5.816 −114.367 −5.637 1.00 211.53 ATOM 2056 CB LYS D 108 7.906 −115.940 −7.291 1.00 207.66 ATOM 2057 CG LYS D 108 6.853 −116.891 −7.874 1.00 216.06 ATOM 2058 CD LYS D 108 7.318 −118.353 −7.932 1.00 219.36 ATOM 2059 CE LYS D 108 7.021 −119.112 −6.653 1.00 223.84 ATOM 2060 NZ LYS D 108 7.844 −120.347 −6.528 1.00 231.67 ATOM 2061 N LEU D 109 5.184 −113.874 −7.744 1.00 208.77 ATOM 2062 CA LEU D 109 3.769 −113.687 −7.437 1.00 210.43 ATOM 2063 C LEU D 109 2.963 −114.893 −7.948 1.00 216.86 ATOM 2064 O LEU D 109 2.945 −115.165 −9.162 1.00 217.24 ATOM 2065 CB LEU D 109 3.192 −112.372 −8.037 1.00 208.67 ATOM 2066 CG LEU D 109 1.685 −112.136 −7.770 1.00 215.64 ATOM 2067 CD1 LEU D 109 1.483 −111.618 −6.405 1.00 216.20 ATOM 2068 CD2 LEU D 109 1.081 −111.163 −8.753 1.00 216.91 ATOM 2069 N GLU D 110 2.292 −115.591 −7.002 1.00 213.68 ATOM 2070 CA GLU D 110 1.368 −116.697 −7.252 1.00 215.12 ATOM 2071 C GLU D 110 −0.069 −116.175 −7.064 1.00 216.63 ATOM 2072 O GLU D 110 −0.266 −115.181 −6.345 1.00 217.00 ATOM 2073 CB GLU D 110 1.645 −117.809 −6.268 1.00 218.29 ATOM 2074 CG GLU D 110 2.682 −118.778 −6.763 1.00 223.34 ATOM 2075 CD GLU D 110 2.011 −120.116 −6.983 1.00 241.29 ATOM 2076 OE1 GLU D 110 2.049 −120.939 −6.042 1.00 231.39 ATOM 2077 OE2 GLU D 110 1.304 −120.275 −8.006 1.00 235.24 ATOM 2078 N ILE D 111 −1.058 −116.786 −7.734 1.00 209.72 ATOM 2079 CA ILE D 111 −2.427 −116.298 −7.592 1.00 209.45 ATOM 2080 C ILE D 111 −3.282 −117.272 −6.841 1.00 213.92 ATOM 2081 O ILE D 111 −3.237 −118.457 −7.146 1.00 216.23 ATOM 2082 CB ILE D 111 −3.038 −115.742 −8.918 1.00 211.76 ATOM 2083 CG1 ILE D 111 −2.371 −114.401 −9.272 1.00 206.29 ATOM 2084 CG2 ILE D 111 −4.569 −115.572 −8.873 1.00 216.45 ATOM 2085 CD1 ILE D 111 −2.039 −114.276 −10.603 1.00 204.47 ATOM 2086 N LYS D 112 −4.034 −116.783 −5.837 1.00 209.55 ATOM 2087 CA LYS D 112 −4.971 −117.588 −5.055 1.00 214.52 ATOM 2088 C LYS D 112 −6.340 −117.653 −5.834 1.00 225.19 ATOM 2089 O LYS D 112 −6.885 −116.609 −6.217 1.00 224.58 ATOM 2090 CB LYS D 112 −5.132 −117.015 −3.634 1.00 215.44 ATOM 2091 CG LYS D 112 −5.190 −118.071 −2.526 1.00 210.41 ATOM 2092 CD LYS D 112 −6.095 −117.694 −1.337 1.00 208.37 ATOM 2093 CE LYS D 112 −6.059 −118.727 −0.235 1.00 210.21 ATOM 2094 NZ LYS D 112 −4.692 −118.905 0.343 1.00 208.55 ATOM 2095 N ARG D 113 −6.833 −118.898 −6.118 1.00 226.17 ATOM 2096 CA ARG D 113 −8.029 −119.303 −6.898 1.00 230.36 ATOM 2097 C ARG D 113 −7.993 −120.819 −7.000 1.00 234.06 ATOM 2098 O ARG D 113 −6.990 −121.445 −6.636 1.00 230.63 ATOM 2099 CB ARG D 113 −7.984 −118.769 −8.364 1.00 229.82 ATOM 2100 CG ARG D 113 −6.619 −119.003 −9.064 1.00 234.74 ATOM 2101 CD ARG D 113 −6.637 −118.853 −10.556 1.00 235.50 ATOM 2102 NE ARG D 113 −6.924 −120.127 −11.198 1.00 236.25 ATOM 2103 CZ ARG D 113 −6.687 −120.385 −12.479 1.00 235.48 ATOM 2104 NH1 ARG D 113 −6.136 −119.452 −13.263 1.00 208.20 ATOM 2105 NH2 ARG D 113 −6.991 −121.577 −12.989 1.00 220.17 ATOM 2106 N ALA D 114 −9.049 −121.409 −7.562 1.00 231.62 ATOM 2107 CA ALA D 114 −9.061 −122.849 −7.801 1.00 234.83 ATOM 2108 C ALA D 114 −8.547 −123.086 −9.225 1.00 244.40 ATOM 2109 O ALA D 114 −8.026 −122.178 −9.886 1.00 190.32 ATOM 2110 CB ALA D 114 −10.464 −123.424 −7.630 1.00 237.35 ATOM 2112 N GLY E 5 27.912 −80.762 −36.382 1.00 190.30 ATOM 2113 CA GLY E 5 29.114 −79.940 −36.433 1.00 191.93 ATOM 2114 C GLY E 5 29.761 −79.669 −35.086 1.00 196.83 ATOM 2115 O GLY E 5 29.401 −80.286 −34.080 1.00 195.48 ATOM 2116 N GLU E 6 30.705 −78.711 −35.051 1.00 195.47 ATOM 2117 CA GLU E 6 31.470 −78.372 −33.845 1.00 194.57 ATOM 2118 C GLU E 6 30.702 −77.628 −32.773 1.00 195.54 ATOM 2119 O GLU E 6 29.643 −77.039 −32.995 1.00 193.14 ATOM 2120 CB GLU E 6 32.749 −77.570 −34.207 1.00 198.44 ATOM 2121 CG GLU E 6 33.928 −77.704 −33.241 1.00 211.27 ATOM 2122 CD GLU E 6 34.262 −79.084 −32.693 1.00 241.32 ATOM 2123 OE1 GLU E 6 34.560 −79.985 −33.510 1.00 249.04 ATOM 2124 OE2 GLU E 6 34.232 −79.262 −31.452 1.00 230.42 ATOM 2125 N VAL E 7 31.266 −77.689 −31.589 1.00 192.06 ATOM 2126 CA VAL E 7 30.891 −76.891 −30.460 1.00 189.19 ATOM 2127 C VAL E 7 31.946 −75.786 −30.491 1.00 199.28 ATOM 2128 O VAL E 7 33.138 −76.061 −30.428 1.00 201.59 ATOM 2129 CB VAL E 7 30.872 −77.656 −29.121 1.00 190.79 ATOM 2130 CG1 VAL E 7 32.072 −78.598 −28.938 1.00 193.75 ATOM 2131 CG2 VAL E 7 30.748 −76.695 −27.947 1.00 187.49 ATOM 2132 N CYS E 8 31.529 −74.554 −30.682 1.00 198.67 ATOM 2133 CA CYS E 8 32.488 −73.462 −30.686 1.00 201.29 ATOM 2134 C CYS E 8 32.291 −72.683 −29.398 1.00 201.30 ATOM 2135 O CYS E 8 31.240 −72.781 −28.771 1.00 199.02 ATOM 2136 CB CYS E 8 32.344 −72.569 −31.916 1.00 204.24 ATOM 2137 SG CYS E 8 32.038 −73.461 −33.461 1.00 211.47 ATOM 2138 N PRO E 9 33.299 −71.936 −28.961 1.00 197.03 ATOM 2139 CA PRO E 9 33.147 −71.179 −27.714 1.00 194.11 ATOM 2140 C PRO E 9 32.463 −69.851 −27.968 1.00 195.35 ATOM 2141 O PRO E 9 32.379 −69.426 −29.121 1.00 195.82 ATOM 2142 CB PRO E 9 34.588 −70.952 −27.293 1.00 198.59 ATOM 2143 CG PRO E 9 35.338 −70.828 −28.622 1.00 206.81 ATOM 2144 CD PRO E 9 34.629 −71.736 −29.582 1.00 202.38 ATOM 2145 N GLY E 10 32.035 −69.184 −26.897 1.00 189.98 ATOM 2146 CA GLY E 10 31.445 −67.856 −26.990 1.00 189.31 ATOM 2147 C GLY E 10 32.311 −66.912 −27.810 1.00 196.49 ATOM 2148 O GLY E 10 33.537 −66.938 −27.684 1.00 199.14 ATOM 2149 N MET E 11 31.683 −66.108 −28.692 1.00 192.03 ATOM 2150 CA MET E 11 32.379 −65.166 −29.562 1.00 193.51 ATOM 2151 C MET E 11 31.907 −63.765 −29.453 1.00 195.34 ATOM 2152 O MET E 11 30.729 −63.504 −29.210 1.00 192.66 ATOM 2153 CB MET E 11 32.337 −65.603 −31.009 1.00 197.71 ATOM 2154 CG MET E 11 32.927 −66.939 −31.196 1.00 202.78 ATOM 2155 SD MET E 11 33.316 −67.250 −32.893 1.00 211.19 ATOM 2156 CE MET E 11 34.526 −68.607 −32.682 1.00 210.07 ATOM 2157 N ASP E 12 32.846 −62.859 −29.715 1.00 193.90 ATOM 2158 CA ASP E 12 32.706 −61.411 −29.626 1.00 194.03 ATOM 2159 C ASP E 12 33.312 −60.813 −30.887 1.00 196.66 ATOM 2160 O ASP E 12 34.519 −60.595 −30.959 1.00 198.31 ATOM 2161 CB ASP E 12 33.418 −60.915 −28.337 1.00 196.74 ATOM 2162 CG ASP E 12 33.175 −59.468 −27.883 1.00 206.69 ATOM 2163 OD2 ASP E 12 33.758 −59.057 −26.838 1.00 209.66 ATOM 2164 OD1 ASP E 12 32.513 −58.720 −28.617 1.00 207.35 ATOM 2165 N ILE E 13 32.464 −60.570 −31.886 1.00 191.03 ATOM 2166 CA ILE E 13 32.863 −60.091 −33.208 1.00 192.87 ATOM 2167 C ILE E 13 32.586 −58.596 −33.365 1.00 194.77 ATOM 2168 O ILE E 13 31.440 −58.168 −33.261 1.00 191.51 ATOM 2169 CB ILE E 13 32.249 −60.995 −34.301 1.00 196.03 ATOM 2170 CG1 ILE E 13 32.430 −62.477 −33.916 1.00 195.15 ATOM 2171 CG2 ILE E 13 32.904 −60.730 −35.650 1.00 200.28 ATOM 2172 CD1 ILE E 13 31.462 −63.378 −34.481 1.00 203.72 ATOM 2173 N ARG E 14 33.670 −57.816 −33.587 1.00 193.23 ATOM 2174 CA ARG E 14 33.711 −56.361 −33.646 1.00 193.96 ATOM 2175 C ARG E 14 34.471 −55.816 −34.836 1.00 200.99 ATOM 2176 O ARG E 14 35.374 −56.474 −35.347 1.00 202.06 ATOM 2177 CB ARG E 14 34.453 −55.833 −32.399 1.00 191.71 ATOM 2178 CG ARG E 14 33.705 −55.993 −31.094 1.00 189.87 ATOM 2179 CD ARG E 14 34.596 −55.826 −29.914 1.00 190.07 ATOM 2180 NE ARG E 14 33.873 −56.184 −28.707 1.00 199.20 ATOM 2181 CZ ARG E 14 33.594 −55.329 −27.729 1.00 216.94 ATOM 2182 NH1 ARG E 14 33.993 −54.060 −27.809 1.00 207.91 ATOM 2183 NH2 ARG E 14 32.912 −55.733 −26.663 1.00 198.07 ATOM 2184 N ASN E 15 34.161 −54.565 −35.209 1.00 199.96 ATOM 2185 CA ASN E 15 34.894 −53.748 −36.179 1.00 204.97 ATOM 2186 C ASN E 15 34.910 −54.183 −37.651 1.00 213.03 ATOM 2187 O ASN E 15 34.493 −53.403 −38.515 1.00 215.01 ATOM 2188 CB ASN E 15 36.331 −53.485 −35.676 1.00 207.54 ATOM 2189 CG ASN E 15 36.406 −53.008 −34.242 1.00 216.10 ATOM 2190 OD1 ASN E 15 35.688 −52.097 −33.819 1.00 206.15 ATOM 2191 ND2 ASN E 15 37.268 −53.622 −33.458 1.00 203.36 ATOM 2192 N ASN E 16 35.452 −55.394 −37.924 1.00 210.46 ATOM 2193 CA ASN E 16 35.647 −56.051 −39.233 1.00 213.61 ATOM 2194 C ASN E 16 34.786 −57.316 −39.320 1.00 218.81 ATOM 2195 O ASN E 16 34.679 −58.046 −38.328 1.00 216.04 ATOM 2196 CB ASN E 16 37.091 −56.632 −39.293 1.00 214.01 ATOM 2197 CG ASN E 16 38.239 −55.953 −40.033 1.00 242.03 ATOM 2198 OD1 ASN E 16 38.056 −54.969 −40.754 1.00 239.62 ATOM 2199 ND2 ASN E 16 39.466 −56.579 −39.858 1.00 240.96 ATOM 2200 N LEU E 17 34.371 −57.709 −40.527 1.00 218.96 ATOM 2201 CA LEU E 17 33.734 −59.013 −40.663 1.00 217.56 ATOM 2202 C LEU E 17 34.717 −60.180 −40.676 1.00 224.83 ATOM 2203 O LEU E 17 34.265 −61.314 −40.585 1.00 221.43 ATOM 2204 CB LEU E 17 32.913 −59.063 −41.924 1.00 219.82 ATOM 2205 CG LEU E 17 31.597 −58.368 −41.832 1.00 223.48 ATOM 2206 CD1 LEU E 17 30.910 −58.391 −43.169 1.00 226.56 ATOM 2207 CD2 LEU E 17 30.724 −59.000 −40.756 1.00 221.66 ATOM 2208 N THR E 18 36.040 −59.936 −40.820 1.00 227.88 ATOM 2209 CA THR E 18 37.034 −61.027 −40.886 1.00 230.30 ATOM 2210 C THR E 18 36.804 −62.178 −39.878 1.00 231.66 ATOM 2211 O THR E 18 36.685 −63.335 −40.283 1.00 231.95 ATOM 2212 CB THR E 18 38.483 −60.514 −40.826 1.00 241.80 ATOM 2213 OG1 THR E 18 38.776 −60.077 −39.491 1.00 240.89 ATOM 2214 CG2 THR E 18 38.775 −59.436 −41.869 1.00 243.03 ATOM 2215 N ARG E 19 36.704 −61.853 −38.587 1.00 224.73 ATOM 2216 CA ARG E 19 36.583 −62.832 −37.505 1.00 221.13 ATOM 2217 C ARG E 19 35.330 −63.703 −37.580 1.00 223.17 ATOM 2218 O ARG E 19 35.301 −64.783 −36.994 1.00 220.80 ATOM 2219 CB ARG E 19 36.636 −62.125 −36.133 1.00 217.49 ATOM 2220 CG ARG E 19 37.883 −61.298 −35.834 1.00 226.76 ATOM 2221 CD ARG E 19 38.075 −61.094 −34.336 1.00 235.47 ATOM 2222 NE ARG E 19 38.089 −62.379 −33.615 1.00 249.17 ATOM 2223 CZ ARG E 19 37.363 −62.645 −32.533 1.00 260.55 ATOM 2224 NH1 ARG E 19 36.611 −61.706 −31.986 1.00 246.40 ATOM 2225 NH2 ARG E 19 37.403 −63.850 −31.975 1.00 242.85 ATOM 2226 N LEU E 20 34.293 −63.213 −38.275 1.00 220.49 ATOM 2227 CA LEU E 20 32.989 −63.863 −38.393 1.00 218.02 ATOM 2228 C LEU E 20 33.027 −65.238 −39.031 1.00 224.59 ATOM 2229 O LEU E 20 32.211 −66.098 −38.698 1.00 222.15 ATOM 2230 CB LEU E 20 32.003 −62.944 −39.117 1.00 218.05 ATOM 2231 CG LEU E 20 30.533 −63.341 −39.105 1.00 218.49 ATOM 2232 CD1 LEU E 20 30.010 −63.581 −37.695 1.00 214.22 ATOM 2233 CD2 LEU E 20 29.723 −62.298 −39.790 1.00 219.46 ATOM 2234 N HIS E 21 33.994 −65.456 −39.911 1.00 225.92 ATOM 2235 CA HIS E 21 34.172 −66.727 −40.588 1.00 228.56 ATOM 2236 C HIS E 21 34.668 −67.819 −39.653 1.00 230.28 ATOM 2237 O HIS E 21 34.638 −68.989 −40.023 1.00 231.01 ATOM 2238 CB HIS E 21 35.061 −66.543 −41.812 1.00 235.48 ATOM 2239 CG HIS E 21 34.549 −65.479 −42.743 1.00 241.44 ATOM 2240 ND1 HIS E 21 33.581 −65.754 −43.699 1.00 244.47 ATOM 2241 CD2 HIS E 21 34.867 −64.165 −42.814 1.00 244.74 ATOM 2242 CE1 HIS E 21 33.367 −64.612 −44.338 1.00 245.81 ATOM 2243 NE2 HIS E 21 34.120 −63.629 −43.846 1.00 246.37 ATOM 2244 N GLU E 22 35.040 −67.448 −38.406 1.00 223.60 ATOM 2245 CA GLU E 22 35.408 −68.410 −37.365 1.00 221.30 ATOM 2246 C GLU E 22 34.196 −69.263 −36.978 1.00 222.53 ATOM 2247 O GLU E 22 34.357 −70.309 −36.342 1.00 221.67 ATOM 2248 CB GLU E 22 35.939 −67.707 −36.120 1.00 220.49 ATOM 2249 CG GLU E 22 37.420 −67.914 −35.903 1.00 231.75 ATOM 2250 CD GLU E 22 38.116 −66.656 −35.436 1.00 251.97 ATOM 2251 OE1 GLU E 22 37.775 −66.173 −34.332 1.00 243.41 ATOM 2252 OE2 GLU E 22 39.063 −66.206 −36.123 1.00 247.26 ATOM 2253 N LEU E 23 32.986 −68.825 −37.364 1.00 217.35 ATOM 2254 CA LEU E 23 31.748 −69.551 −37.082 1.00 214.21 ATOM 2255 C LEU E 23 31.372 −70.555 −38.151 1.00 221.41 ATOM 2256 O LEU E 23 30.379 −71.270 −37.981 1.00 219.32 ATOM 2257 CB LEU E 23 30.588 −68.559 −36.941 1.00 211.66 ATOM 2258 CG LEU E 23 30.644 −67.668 −35.738 1.00 213.96 ATOM 2259 CD1 LEU E 23 29.462 −66.731 −35.719 1.00 211.96 ATOM 2260 CD2 LEU E 23 30.711 −68.506 −34.477 1.00 215.69 ATOM 2261 N GLU E 24 32.118 −70.586 −39.271 1.00 222.24 ATOM 2262 CA GLU E 24 31.756 −71.401 −40.422 1.00 224.40 ATOM 2263 C GLU E 24 31.467 −72.878 −40.175 1.00 226.88 ATOM 2264 O GLU E 24 30.574 −73.414 −40.819 1.00 227.07 ATOM 2265 CB GLU E 24 32.683 −71.169 −41.604 1.00 230.80 ATOM 2266 CG GLU E 24 34.049 −71.821 −41.473 1.00 243.35 ATOM 2267 CD GLU E 24 34.958 −71.526 −42.649 1.00 266.86 ATOM 2268 OE1 GLU E 24 34.680 −70.559 −43.391 1.00 259.23 ATOM 2269 OE2 GLU E 24 35.948 −72.267 −42.837 1.00 265.59 ATOM 2270 N ASN E 25 32.188 −73.522 −39.245 1.00 221.65 ATOM 2271 CA ASN E 25 31.979 −74.919 −38.891 1.00 220.65 ATOM 2272 C ASN E 25 31.492 −74.881 −37.462 0.70 218.45 ATOM 2273 O ASN E 25 32.292 −74.953 −36.524 0.70 216.67 ATOM 2274 CB ASN E 25 33.284 −75.728 −39.030 1.00 226.31 ATOM 2275 CG ASN E 25 34.021 −75.610 −40.369 1.00 251.67 ATOM 2276 OD1 ASN E 25 33.444 −75.728 −41.464 1.00 245.70 ATOM 2277 ND2 ASN E 25 35.338 −75.400 −40.293 1.00 246.35 ATOM 2278 N CYS E 26 30.177 −74.669 −37.296 1.00 212.32 ATOM 2279 CA CYS E 26 29.587 −74.494 −35.965 1.00 208.26 ATOM 2280 C CYS E 26 28.104 −74.852 −35.833 1.00 207.15 ATOM 2281 O CYS E 26 27.267 −74.237 −36.493 1.00 206.78 ATOM 2282 CB CYS E 26 29.843 −73.074 −35.470 1.00 207.62 ATOM 2283 SG CYS E 26 30.083 −72.950 −33.687 1.00 208.34 ATOM 2284 N SER E 27 27.780 −75.761 −34.894 1.00 198.98 ATOM 2285 CA SER E 27 26.405 −76.160 −34.617 1.00 195.08 ATOM 2286 C SER E 27 25.891 −75.518 −33.378 1.00 192.07 ATOM 2287 O SER E 27 24.737 −75.093 −33.327 1.00 188.85 ATOM 2288 CB SER E 27 26.311 −77.667 −34.458 1.00 199.87 ATOM 2289 OG SER E 27 26.007 −78.232 −35.720 1.00 213.74 ATOM 2290 N VAL E 28 26.725 −75.516 −32.347 1.00 187.21 ATOM 2291 CA VAL E 28 26.392 −74.968 −31.051 1.00 184.64 ATOM 2292 C VAL E 28 27.454 −73.975 −30.689 1.00 188.85 ATOM 2293 O VAL E 28 28.629 −74.295 −30.774 1.00 190.85 ATOM 2294 CB VAL E 28 26.351 −76.082 −29.953 1.00 188.60 ATOM 2295 CG1 VAL E 28 26.108 −75.503 −28.563 1.00 185.75 ATOM 2296 CG2 VAL E 28 25.306 −77.144 −30.252 1.00 188.82 ATOM 2297 N ILE E 29 27.066 −72.806 −30.223 1.00 184.12 ATOM 2298 CA ILE E 29 28.014 −71.870 −29.641 1.00 184.41 ATOM 2299 C ILE E 29 27.829 −72.042 −28.125 1.00 189.86 ATOM 2300 O ILE E 29 26.751 −71.766 −27.583 1.00 190.05 ATOM 2301 CB ILE E 29 27.822 −70.413 −30.104 1.00 186.88 ATOM 2302 CG1 ILE E 29 28.375 −70.236 −31.528 1.00 189.31 ATOM 2303 CG2 ILE E 29 28.493 −69.436 −29.112 1.00 186.14 ATOM 2304 CD1 ILE E 29 27.912 −68.987 −32.200 1.00 192.49 ATOM 2305 N GLU E 30 28.860 −72.538 −27.453 1.00 186.81 ATOM 2306 CA GLU E 30 28.823 −72.802 −26.018 1.00 185.57 ATOM 2307 C GLU E 30 29.345 −71.539 −25.372 1.00 191.48 ATOM 2308 O GLU E 30 30.558 −71.336 −25.288 1.00 194.45 ATOM 2309 CB GLU E 30 29.688 −74.044 −25.734 1.00 188.36 ATOM 2310 CG GLU E 30 29.660 −74.566 −24.311 1.00 194.02 ATOM 2311 CD GLU E 30 30.392 −75.875 −24.111 1.00 199.03 ATOM 2312 OE1 GLU E 30 31.614 −75.912 −24.375 1.00 215.71 ATOM 2313 OE2 GLU E 30 29.739 −76.875 −23.741 1.00 167.96 ATOM 2314 N GLY E 31 28.414 −70.665 −25.011 1.00 186.77 ATOM 2315 CA GLY E 31 28.691 −69.299 −24.574 1.00 187.62 ATOM 2316 C GLY E 31 27.776 −68.312 −25.305 1.00 191.54 ATOM 2317 O GLY E 31 26.683 −68.692 −25.755 1.00 193.21 ATOM 2318 N HIS E 32 28.175 −67.036 −25.423 1.00 183.86 ATOM 2319 CA HIS E 32 27.309 −66.073 −26.097 1.00 181.26 ATOM 2320 C HIS E 32 27.808 −65.743 −27.484 1.00 182.85 ATOM 2321 O HIS E 32 28.927 −66.115 −27.835 1.00 185.20 ATOM 2322 CB HIS E 32 27.177 −64.796 −25.255 1.00 181.54 ATOM 2323 CG HIS E 32 28.473 −64.104 −25.001 1.00 186.07 ATOM 2324 ND1 HIS E 32 28.933 −63.901 −23.721 1.00 187.47 ATOM 2325 CD2 HIS E 32 29.363 −63.581 −25.879 1.00 189.88 ATOM 2326 CE1 HIS E 32 30.092 −63.281 −23.853 1.00 188.92 ATOM 2327 NE2 HIS E 32 30.388 −63.061 −25.137 1.00 190.66 ATOM 2328 N LEU E 33 26.988 −65.024 −28.264 1.00 174.23 ATOM 2329 CA LEU E 33 27.397 −64.510 −29.549 1.00 173.06 ATOM 2330 C LEU E 33 27.045 −63.057 −29.552 1.00 175.61 ATOM 2331 O LEU E 33 25.870 −62.713 −29.418 1.00 173.66 ATOM 2332 CB LEU E 33 26.742 −65.241 −30.728 1.00 172.19 ATOM 2333 CG LEU E 33 27.166 −64.773 −32.121 1.00 177.04 ATOM 2334 CD1 LEU E 33 28.656 −64.738 −32.279 1.00 177.86 ATOM 2335 CD2 LEU E 33 26.562 −65.599 −33.180 1.00 179.00 ATOM 2336 N GLN E 34 28.073 −62.207 −29.632 1.00 173.47 ATOM 2337 CA GLN E 34 27.942 −60.759 −29.755 1.00 174.45 ATOM 2338 C GLN E 34 28.561 −60.343 −31.103 1.00 181.80 ATOM 2339 O GLN E 34 29.724 −60.665 −31.380 1.00 185.61 ATOM 2340 CB GLN E 34 28.663 −60.015 −28.622 1.00 175.69 ATOM 2341 CG GLN E 34 28.107 −60.200 −27.221 1.00 189.85 ATOM 2342 CD GLN E 34 28.846 −59.389 −26.162 1.00 207.69 ATOM 2343 OE1 GLN E 34 28.478 −59.395 −24.983 1.00 205.33 ATOM 2344 NE2 GLN E 34 29.914 −58.690 −26.544 1.00 197.23 ATOM 2345 N ILE E 35 27.773 −59.663 −31.951 1.00 176.21 ATOM 2346 CA ILE E 35 28.236 −59.111 −33.217 1.00 178.19 ATOM 2347 C ILE E 35 27.950 −57.637 −33.107 1.00 185.67 ATOM 2348 O ILE E 35 26.789 −57.238 −32.939 1.00 184.68 ATOM 2349 CB ILE E 35 27.600 −59.743 −34.452 1.00 180.97 ATOM 2350 CG1 ILE E 35 27.684 −61.263 −34.394 1.00 178.55 ATOM 2351 CG2 ILE E 35 28.268 −59.180 −35.722 1.00 186.08 ATOM 2352 CD1 ILE E 35 26.981 −61.971 −35.497 1.00 183.95 ATOM 2353 N LEU E 36 29.007 −56.824 −33.154 1.00 186.01 ATOM 2354 CA LEU E 36 28.841 −55.418 −32.872 1.00 188.00 ATOM 2355 C LEU E 36 29.854 −54.463 −33.440 1.00 194.09 ATOM 2356 O LEU E 36 30.974 −54.824 −33.793 1.00 195.15 ATOM 2357 CB LEU E 36 28.735 −55.209 −31.329 1.00 186.42 ATOM 2358 CG LEU E 36 29.940 −55.531 −30.446 1.00 191.59 ATOM 2359 CD1 LEU E 36 29.782 −54.895 −29.103 1.00 191.87 ATOM 2360 CD2 LEU E 36 30.075 −56.989 −30.204 1.00 190.62 ATOM 2361 N LEU E 37 29.447 −53.206 −33.434 1.00 191.02 ATOM 2362 CA LEU E 37 30.281 −52.099 −33.777 1.00 194.35 ATOM 2363 C LEU E 37 30.990 −52.258 −35.128 1.00 205.69 ATOM 2364 O LEU E 37 32.214 −52.182 −35.222 1.00 207.67 ATOM 2365 CB LEU E 37 31.244 −51.804 −32.607 1.00 193.19 ATOM 2366 CG LEU E 37 30.612 −51.458 −31.264 1.00 194.32 ATOM 2367 CD1 LEU E 37 31.625 −51.555 −30.167 1.00 192.32 ATOM 2368 CD2 LEU E 37 30.010 −50.072 −31.283 1.00 201.76 ATOM 2369 N MET E 38 30.194 −52.465 −36.178 1.00 205.24 ATOM 2370 CA MET E 38 30.674 −52.532 −37.556 1.00 208.91 ATOM 2371 C MET E 38 30.133 −51.379 −38.316 1.00 213.96 ATOM 2372 O MET E 38 29.020 −51.415 −38.844 1.00 213.31 ATOM 2373 CB MET E 38 30.330 −53.850 −38.166 1.00 210.41 ATOM 2374 CG MET E 38 31.136 −54.859 −37.507 1.00 212.57 ATOM 2375 SD MET E 38 30.965 −56.474 −38.132 1.00 216.21 ATOM 2376 CE MET E 38 31.890 −57.271 −36.932 1.00 210.50 ATOM 2377 N PHE E 39 30.926 −50.324 −38.318 1.00 211.67 ATOM 2378 CA PHE E 39 30.538 −49.050 −38.856 1.00 214.01 ATOM 2379 C PHE E 39 30.725 −48.879 −40.337 1.00 220.85 ATOM 2380 O PHE E 39 30.068 −48.011 −40.918 1.00 223.10 ATOM 2381 CB PHE E 39 31.258 −47.940 −38.109 1.00 216.79 ATOM 2382 CG PHE E 39 30.981 −47.854 −36.631 1.00 214.43 ATOM 2383 CD1 PHE E 39 32.009 −47.685 −35.728 1.00 218.04 ATOM 2384 CD2 PHE E 39 29.695 −47.958 −36.141 1.00 212.97 ATOM 2385 CE1 PHE E 39 31.753 −47.550 −34.363 1.00 216.47 ATOM 2386 CE2 PHE E 39 29.446 −47.862 −34.773 1.00 213.33 ATOM 2387 CZ PHE E 39 30.476 −47.655 −33.891 1.00 211.86 ATOM 2388 N LYS E 40 31.620 −49.665 −40.958 1.00 216.91 ATOM 2389 CA LYS E 40 31.898 −49.475 −42.383 1.00 220.65 ATOM 2390 C LYS E 40 31.346 −50.530 −43.329 1.00 222.92 ATOM 2391 O LYS E 40 31.478 −50.405 −44.553 1.00 224.72 ATOM 2392 CB LYS E 40 33.377 −49.150 −42.637 1.00 226.35 ATOM 2393 CG LYS E 40 33.757 −47.711 −42.249 1.00 231.72 ATOM 2394 CD LYS E 40 35.116 −47.256 −42.817 1.00 236.87 ATOM 2395 CE LYS E 40 36.353 −47.900 −42.205 1.00 234.87 ATOM 2396 NZ LYS E 40 36.489 −47.639 −40.743 1.00 231.80 ATOM 2397 N THR E 41 30.683 −51.544 −42.760 1.00 216.48 ATOM 2398 CA THR E 41 30.031 −52.612 −43.518 1.00 216.23 ATOM 2399 C THR E 41 28.849 −52.045 −44.331 1.00 222.87 ATOM 2400 O THR E 41 28.281 −50.999 −43.977 1.00 223.52 ATOM 2401 CB THR E 41 29.660 −53.820 −42.608 1.00 217.13 ATOM 2402 OG1 THR E 41 29.104 −53.363 −41.371 1.00 212.47 ATOM 2403 CG2 THR E 41 30.854 −54.681 −42.278 1.00 214.22 ATOM 2404 N ARG E 42 28.520 −52.721 −45.445 1.00 220.22 ATOM 2405 CA ARG E 42 27.473 −52.327 −46.376 1.00 221.62 ATOM 2406 C ARG E 42 26.653 −53.567 −46.756 1.00 224.84 ATOM 2407 O ARG E 42 27.093 −54.685 −46.488 1.00 223.17 ATOM 2408 CB ARG E 42 28.113 −51.682 −47.612 1.00 224.41 ATOM 2409 CG ARG E 42 29.142 −50.605 −47.288 1.00 230.96 ATOM 2410 CD ARG E 42 30.525 −50.980 −47.788 1.00 236.77 ATOM 2411 NE ARG E 42 30.995 −50.017 −48.789 1.00 244.00 ATOM 2412 CZ ARG E 42 32.134 −50.119 −49.469 1.00 249.77 ATOM 2413 NH1 ARG E 42 32.941 −51.155 −49.274 1.00 233.66 ATOM 2414 NH2 ARG E 42 32.475 −49.183 −50.349 1.00 241.43 ATOM 2415 N PRO E 43 25.442 −53.409 −47.323 1.00 222.40 ATOM 2416 CA PRO E 43 24.621 −54.594 −47.656 1.00 220.77 ATOM 2417 C PRO E 43 25.313 −55.669 −48.502 1.00 227.06 ATOM 2418 O PRO E 43 25.099 −56.866 −48.281 1.00 224.64 ATOM 2419 CB PRO E 43 23.414 −53.988 −48.366 1.00 225.14 ATOM 2420 CG PRO E 43 23.326 −52.591 −47.841 1.00 230.23 ATOM 2421 CD PRO E 43 24.735 −52.154 −47.650 1.00 226.84 ATOM 2422 N GLU E 44 26.191 −55.235 −49.420 1.00 228.77 ATOM 2423 CA GLU E 44 26.958 −56.117 −50.299 1.00 231.78 ATOM 2424 C GLU E 44 27.824 −57.103 −49.533 1.00 233.10 ATOM 2425 O GLU E 44 28.011 −58.217 −50.009 1.00 233.75 ATOM 2426 CB GLU E 44 27.803 −55.316 −51.296 1.00 239.38 ATOM 2427 CG GLU E 44 28.774 −54.336 −50.645 1.00 253.39 ATOM 2428 CD GLU E 44 29.113 −53.072 −51.414 1.00 277.00 ATOM 2429 OE1 GLU E 44 28.651 −52.908 −52.568 1.00 277.81 ATOM 2430 OE2 GLU E 44 29.855 −52.238 −50.848 1.00 275.47 ATOM 2431 N ASP E 45 28.320 −56.709 −48.343 1.00 226.13 ATOM 2432 CA ASP E 45 29.135 −57.560 −47.480 1.00 222.52 ATOM 2433 C ASP E 45 28.328 −58.734 −46.895 1.00 219.85 ATOM 2434 O ASP E 45 28.909 −59.735 −46.484 1.00 216.59 ATOM 2435 CB ASP E 45 29.787 −56.708 −46.373 1.00 223.04 ATOM 2436 CG ASP E 45 30.761 −55.657 −46.909 1.00 241.04 ATOM 2437 OD1 ASP E 45 30.306 −54.732 −47.630 1.00 244.07 ATOM 2438 OD2 ASP E 45 31.988 −55.831 −46.728 1.00 250.01 ATOM 2439 N PHE E 46 26.998 −58.626 −46.891 1.00 215.66 ATOM 2440 CA PHE E 46 26.102 −59.638 −46.343 1.00 212.72 ATOM 2441 C PHE E 46 25.268 −60.390 −47.371 1.00 222.83 ATOM 2442 O PHE E 46 24.539 −61.313 −47.004 1.00 218.72 ATOM 2443 CB PHE E 46 25.181 −59.002 −45.297 1.00 210.92 ATOM 2444 CG PHE E 46 25.912 −58.340 −44.158 1.00 210.43 ATOM 2445 CD2 PHE E 46 25.721 −56.995 −43.880 1.00 213.14 ATOM 2446 CD1 PHE E 46 26.818 −59.056 −43.380 1.00 211.07 ATOM 2447 CE2 PHE E 46 26.412 −56.382 −42.835 1.00 214.23 ATOM 2448 CE1 PHE E 46 27.489 −58.448 −42.323 1.00 210.11 ATOM 2449 CZ PHE E 46 27.280 −57.121 −42.055 1.00 209.86 ATOM 2450 N ARG E 47 25.358 −60.007 −48.651 1.00 229.04 ATOM 2451 CA ARG E 47 24.618 −60.683 −49.736 1.00 233.12 ATOM 2452 C ARG E 47 25.021 −62.169 −49.896 1.00 241.29 ATOM 2453 O ARG E 47 24.177 −63.009 −50.238 1.00 240.96 ATOM 2454 CB ARG E 47 24.843 −59.966 −51.073 1.00 237.88 ATOM 2455 CG ARG E 47 24.190 −58.604 −51.172 1.00 247.35 ATOM 2456 CD ARG E 47 24.204 −58.178 −52.615 1.00 266.76 ATOM 2457 NE ARG E 47 25.502 −57.624 −53.013 1.00 274.69 ATOM 2458 CZ ARG E 47 26.342 −58.186 −53.879 1.00 283.07 ATOM 2459 NH1 ARG E 47 26.033 −59.339 −54.463 1.00 273.99 ATOM 2460 NH2 ARG E 47 27.494 −57.597 −54.172 1.00 270.92 ATOM 2461 N ASP E 48 26.318 −62.466 −49.630 1.00 240.30 ATOM 2462 CA ASP E 48 27.009 −63.764 −49.769 1.00 240.95 ATOM 2463 C ASP E 48 27.293 −64.480 −48.452 1.00 238.74 ATOM 2464 O ASP E 48 28.084 −65.429 −48.442 1.00 238.53 ATOM 2465 CB ASP E 48 28.372 −63.537 −50.510 1.00 247.94 ATOM 2466 CG ASP E 48 29.584 −63.095 −49.647 1.00 257.66 ATOM 2467 OD1 ASP E 48 30.715 −63.578 −49.909 1.00 260.92 ATOM 2468 OD2 ASP E 48 29.387 −62.299 −48.688 1.00 259.51 ATOM 2469 N LEU E 49 26.711 −64.019 −47.354 1.00 230.65 ATOM 2470 CA LEU E 49 27.059 −64.490 −46.027 1.00 226.23 ATOM 2471 C LEU E 49 25.960 −65.271 −45.316 1.00 227.93 ATOM 2472 O LEU E 49 24.854 −64.768 −45.110 1.00 225.98 ATOM 2473 CB LEU E 49 27.507 −63.260 −45.238 1.00 224.43 ATOM 2474 CG LEU E 49 28.515 −63.451 −44.151 1.00 225.71 ATOM 2475 CD1 LEU E 49 29.763 −64.144 −44.667 1.00 228.97 ATOM 2476 CD2 LEU E 49 28.868 −62.120 −43.570 1.00 225.36 ATOM 2477 N SER E 50 26.282 −66.511 −44.942 1.00 223.93 ATOM 2478 CA SER E 50 25.344 −67.430 −44.321 1.00 220.52 ATOM 2479 C SER E 50 26.045 −68.407 −43.399 1.00 224.01 ATOM 2480 O SER E 50 27.121 −68.908 −43.746 1.00 226.92 ATOM 2481 CB SER E 50 24.625 −68.228 −45.405 1.00 225.59 ATOM 2482 OG SER E 50 23.463 −68.843 −44.880 1.00 230.25 ATOM 2483 N PHE E 51 25.417 −68.707 −42.240 1.00 216.19 ATOM 2484 CA PHE E 51 25.893 −69.705 −41.273 1.00 213.82 ATOM 2485 C PHE E 51 24.761 −70.696 −40.990 1.00 215.45 ATOM 2486 O PHE E 51 24.155 −70.687 −39.912 1.00 211.83 ATOM 2487 CB PHE E 51 26.445 −69.047 −40.011 1.00 213.12 ATOM 2488 CG PHE E 51 27.612 −68.169 −40.350 1.00 217.61 ATOM 2489 CD1 PHE E 51 28.866 −68.719 −40.612 1.00 223.97 ATOM 2490 CD2 PHE E 51 27.443 −66.802 −40.508 1.00 220.59 ATOM 2491 CE1 PHE E 51 29.951 −67.902 −40.972 1.00 227.81 ATOM 2492 CE2 PHE E 51 28.521 −65.986 −40.866 1.00 226.40 ATOM 2493 CZ PHE E 51 29.771 −66.539 −41.094 1.00 226.94 ATOM 2494 N PRO E 52 24.468 −71.563 −41.988 1.00 214.14 ATOM 2495 CA PRO E 52 23.326 −72.471 −41.874 1.00 212.52 ATOM 2496 C PRO E 52 23.517 −73.593 −40.886 1.00 214.19 ATOM 2497 O PRO E 52 22.547 −74.268 −40.559 1.00 212.68 ATOM 2498 CB PRO E 52 23.183 −73.015 −43.292 1.00 218.25 ATOM 2499 CG PRO E 52 24.571 −73.016 −43.819 1.00 225.74 ATOM 2500 CD PRO E 52 25.142 −71.737 −43.289 1.00 220.21 ATOM 2501 N LYS E 53 24.761 −73.802 −40.433 1.00 209.82 ATOM 2502 CA LYS E 53 25.087 −74.833 −39.459 1.00 206.87 ATOM 2503 C LYS E 53 24.665 −74.466 −38.042 1.00 204.87 ATOM 2504 O LYS E 53 24.495 −75.377 −37.234 1.00 203.12 ATOM 2505 CB LYS E 53 26.589 −75.157 −39.480 1.00 210.62 ATOM 2506 CG LYS E 53 27.036 −75.989 −40.658 1.00 221.74 ATOM 2507 CD LYS E 53 28.508 −76.418 −40.454 1.00 231.38 ATOM 2508 CE LYS E 53 28.989 −77.503 −41.403 1.00 248.74 ATOM 2509 NZ LYS E 53 30.481 −77.546 −41.497 1.00 260.38 ATOM 2510 N LEU E 54 24.557 −73.166 −37.709 1.00 197.84 ATOM 2511 CA LEU E 54 24.226 −72.750 −36.348 1.00 193.01 ATOM 2512 C LEU E 54 22.796 −73.053 −35.943 1.00 191.32 ATOM 2513 O LEU E 54 21.854 −72.573 −36.573 1.00 190.05 ATOM 2514 CB LEU E 54 24.584 −71.293 −36.116 1.00 192.64 ATOM 2515 CG LEU E 54 24.456 −70.815 −34.687 1.00 194.02 ATOM 2516 CD1 LEU E 54 25.467 −71.507 −33.776 1.00 194.20 ATOM 2517 CD2 LEU E 54 24.615 −69.334 −34.626 1.00 194.58 ATOM 2518 N ILE E 55 22.654 −73.878 −34.899 1.00 184.72 ATOM 2519 CA ILE E 55 21.369 −74.357 −34.414 1.00 182.14 ATOM 2520 C ILE E 55 21.089 −73.777 −33.071 1.00 181.29 ATOM 2521 O ILE E 55 19.931 −73.504 −32.736 1.00 179.11 ATOM 2522 CB ILE E 55 21.356 −75.912 −34.335 1.00 185.99 ATOM 2523 CG1 ILE E 55 21.665 −76.548 −35.693 1.00 190.47 ATOM 2524 CG2 ILE E 55 20.034 −76.450 −33.795 1.00 184.36 ATOM 2525 CD1 ILE E 55 22.781 −77.507 −35.665 1.00 204.18 ATOM 2526 N MET E 56 22.134 −73.590 −32.287 1.00 176.70 ATOM 2527 CA MET E 56 21.905 −73.194 −30.930 1.00 175.02 ATOM 2528 C MET E 56 23.007 −72.361 −30.309 1.00 178.16 ATOM 2529 O MET E 56 24.178 −72.611 −30.569 1.00 179.68 ATOM 2530 CB MET E 56 21.792 −74.492 −30.151 1.00 177.15 ATOM 2531 CG MET E 56 20.912 −74.424 −28.978 1.00 179.44 ATOM 2532 SD MET E 56 21.562 −75.340 −27.563 1.00 183.29 ATOM 2533 CE MET E 56 22.142 −76.951 −28.344 1.00 181.96 ATOM 2534 N ILE E 57 22.629 −71.424 −29.430 1.00 171.34 ATOM 2535 CA ILE E 57 23.538 −70.593 −28.640 1.00 169.98 ATOM 2536 C ILE E 57 23.170 −70.873 −27.176 1.00 174.04 ATOM 2537 O ILE E 57 21.995 −70.764 −26.836 1.00 175.13 ATOM 2538 CB ILE E 57 23.366 −69.112 −29.013 1.00 172.38 ATOM 2539 CG1 ILE E 57 23.758 −68.891 −30.477 1.00 174.79 ATOM 2540 CG2 ILE E 57 24.157 −68.217 −28.058 1.00 170.82 ATOM 2541 CD1 ILE E 57 23.390 −67.534 −31.079 1.00 182.82 ATOM 2542 N THR E 58 24.119 −71.256 −26.317 1.00 168.58 ATOM 2543 CA THR E 58 23.776 −71.595 −24.928 1.00 166.65 ATOM 2544 C THR E 58 23.419 −70.383 −24.055 1.00 170.17 ATOM 2545 O THR E 58 22.624 −70.497 −23.118 1.00 167.37 ATOM 2546 CB THR E 58 24.911 −72.407 −24.329 1.00 171.53 ATOM 2547 OG1 THR E 58 25.212 −73.507 −25.198 1.00 168.23 ATOM 2548 CG2 THR E 58 24.693 −72.788 −22.862 1.00 169.84 ATOM 2549 N ASP E 59 24.041 −69.241 −24.333 1.00 169.85 ATOM 2550 CA ASP E 59 23.826 −68.046 −23.523 1.00 170.97 ATOM 2551 C ASP E 59 22.881 −67.066 −24.198 1.00 176.29 ATOM 2552 O ASP E 59 21.666 −67.253 −24.152 1.00 177.93 ATOM 2553 CB ASP E 59 25.169 −67.380 −23.124 1.00 174.96 ATOM 2554 CG ASP E 59 26.064 −68.215 −22.203 1.00 197.37 ATOM 2555 OD1 ASP E 59 25.616 −69.303 −21.752 1.00 200.42 ATOM 2556 OD2 ASP E 59 27.214 −67.783 −21.930 1.00 205.45 ATOM 2557 N TYR E 60 23.420 −66.030 −24.832 1.00 170.89 ATOM 2558 CA TYR E 60 22.593 −65.026 −25.475 1.00 169.59 ATOM 2559 C TYR E 60 23.161 −64.595 −26.839 1.00 173.76 ATOM 2560 O TYR E 60 24.348 −64.814 −27.137 1.00 175.28 ATOM 2561 CB TYR E 60 22.408 −63.824 −24.527 1.00 170.01 ATOM 2562 CG TYR E 60 23.692 −63.093 −24.218 1.00 171.92 ATOM 2563 CD1 TYR E 60 24.237 −62.178 −25.123 1.00 175.00 ATOM 2564 CD2 TYR E 60 24.352 −63.289 −23.013 1.00 172.85 ATOM 2565 CE1 TYR E 60 25.427 −61.513 −24.851 1.00 176.57 ATOM 2566 CE2 TYR E 60 25.543 −62.626 −22.727 1.00 175.77 ATOM 2567 CZ TYR E 60 26.073 −61.738 −23.647 1.00 186.72 ATOM 2568 OH TYR E 60 27.235 −61.087 −23.333 1.00 193.30 ATOM 2569 N LEU E 61 22.297 −63.951 −27.651 1.00 167.80 ATOM 2570 CA LEU E 61 22.629 −63.354 −28.948 1.00 166.94 ATOM 2571 C LEU E 61 22.429 −61.856 −28.835 1.00 165.03 ATOM 2572 O LEU E 61 21.343 −61.409 −28.472 1.00 162.44 ATOM 2573 CB LEU E 61 21.721 −63.895 −30.057 1.00 167.08 ATOM 2574 CG LEU E 61 21.944 −63.361 −31.451 1.00 172.98 ATOM 2575 CD1 LEU E 61 23.396 −63.592 −31.907 1.00 174.51 ATOM 2576 CD2 LEU E 61 20.942 −63.965 −32.413 1.00 173.73 ATOM 2577 N LEU E 62 23.480 −61.099 −29.128 1.00 160.27 ATOM 2578 CA LEU E 62 23.474 −59.647 −29.093 1.00 160.75 ATOM 2579 C LEU E 62 24.011 −59.057 −30.408 1.00 169.79 ATOM 2580 O LEU E 62 25.129 −59.366 −30.836 1.00 170.96 ATOM 2581 CB LEU E 62 24.265 −59.150 −27.878 1.00 159.45 ATOM 2582 CG LEU E 62 24.775 −57.705 −27.808 1.00 164.24 ATOM 2583 CD1 LEU E 62 23.703 −56.628 −27.963 1.00 164.66 ATOM 2584 CD2 LEU E 62 25.523 −57.507 −26.557 1.00 165.61 ATOM 2585 N LEU E 63 23.185 −58.208 −31.049 1.00 167.84 ATOM 2586 CA LEU E 63 23.515 −57.499 −32.286 1.00 169.68 ATOM 2587 C LEU E 63 23.325 −56.012 −31.991 1.00 175.72 ATOM 2588 O LEU E 63 22.253 −55.562 −31.553 1.00 174.17 ATOM 2589 CB LEU E 63 22.631 −57.919 −33.472 1.00 169.93 ATOM 2590 CG LEU E 63 22.750 −59.299 −34.142 1.00 172.66 ATOM 2591 CD1 LEU E 63 24.143 −59.765 −34.310 1.00 172.03 ATOM 2592 CD2 LEU E 63 21.988 −60.315 −33.419 1.00 173.40 ATOM 2593 N PHE E 64 24.400 −55.261 −32.195 1.00 175.49 ATOM 2594 CA PHE E 64 24.453 −53.844 −31.870 1.00 177.54 ATOM 2595 C PHE E 64 25.294 −53.082 −32.877 1.00 179.72 ATOM 2596 O PHE E 64 26.457 −53.412 −33.096 1.00 180.08 ATOM 2597 CB PHE E 64 25.024 −53.674 −30.434 1.00 179.15 ATOM 2598 CG PHE E 64 25.415 −52.279 −30.000 1.00 184.16 ATOM 2599 CD1 PHE E 64 24.447 −51.305 −29.764 1.00 189.52 ATOM 2600 CD2 PHE E 64 26.745 −51.949 −29.793 1.00 188.36 ATOM 2601 CE1 PHE E 64 24.810 −50.012 −29.360 1.00 193.78 ATOM 2602 CE2 PHE E 64 27.104 −50.658 −29.389 1.00 194.53 ATOM 2603 CZ PHE E 64 26.134 −49.700 −29.176 1.00 194.39 ATOM 2604 N ARG E 65 24.726 −52.062 −33.489 1.00 174.49 ATOM 2605 CA ARG E 65 25.504 −51.262 −34.420 1.00 176.37 ATOM 2606 C ARG E 65 26.229 −52.050 −35.538 1.00 182.13 ATOM 2607 O ARG E 65 27.423 −51.865 −35.729 1.00 183.65 ATOM 2608 CB ARG E 65 26.482 −50.346 −33.651 1.00 172.01 ATOM 2609 CG ARG E 65 25.829 −49.285 −32.784 1.00 169.53 ATOM 2610 CD ARG E 65 25.318 −48.107 −33.575 1.00 173.21 ATOM 2611 NE ARG E 65 24.904 −47.037 −32.674 1.00 177.78 ATOM 2612 CZ ARG E 65 24.674 −45.784 −33.052 1.00 204.44 ATOM 2613 NH1 ARG E 65 24.793 −45.434 −34.334 1.00 204.01 ATOM 2614 NH2 ARG E 65 24.333 −44.867 −32.155 1.00 189.35 ATOM 2615 N VAL E 66 25.514 −52.910 −36.269 1.00 178.46 ATOM 2616 CA VAL E 66 26.086 −53.646 −37.402 1.00 179.53 ATOM 2617 C VAL E 66 25.443 −53.027 −38.645 1.00 190.01 ATOM 2618 O VAL E 66 24.255 −53.251 −38.947 1.00 186.65 ATOM 2619 CB VAL E 66 25.922 −55.189 −37.324 1.00 178.89 ATOM 2620 CG1 VAL E 66 26.557 −55.875 −38.528 1.00 180.23 ATOM 2621 CG2 VAL E 66 26.499 −55.744 −36.024 1.00 175.16 ATOM 2622 N TYR E 67 26.227 −52.176 −39.318 1.00 195.82 ATOM 2623 CA TYR E 67 25.773 −51.423 −40.487 1.00 201.79 ATOM 2624 C TYR E 67 25.695 −52.298 −41.732 1.00 211.76 ATOM 2625 O TYR E 67 26.472 −53.249 −41.892 1.00 210.90 ATOM 2626 CB TYR E 67 26.632 −50.170 −40.721 1.00 206.21 ATOM 2627 CG TYR E 67 26.453 −49.088 −39.675 1.00 207.15 ATOM 2628 CD2 TYR E 67 26.306 −47.761 −40.042 1.00 212.69 ATOM 2629 CD1 TYR E 67 26.504 −49.385 −38.312 1.00 204.56 ATOM 2630 CE2 TYR E 67 26.197 −46.752 −39.085 1.00 214.55 ATOM 2631 CE1 TYR E 67 26.364 −48.390 −37.346 1.00 204.99 ATOM 2632 CZ TYR E 67 26.217 −47.072 −37.737 1.00 219.62 ATOM 2633 OH TYR E 67 26.121 −46.075 −36.795 1.00 224.11 ATOM 2634 N GLY E 68 24.711 −52.005 −42.573 1.00 212.80 ATOM 2635 CA GLY E 68 24.493 −52.743 −43.812 1.00 215.07 ATOM 2636 C GLY E 68 23.714 −54.039 −43.681 1.00 215.47 ATOM 2637 O GLY E 68 23.319 −54.609 −44.698 1.00 217.98 ATOM 2638 N LEU E 69 23.480 −54.528 −42.446 1.00 205.53 ATOM 2639 CA LEU E 69 22.736 −55.771 −42.236 1.00 201.74 ATOM 2640 C LEU E 69 21.254 −55.460 −42.192 1.00 205.34 ATOM 2641 O LEU E 69 20.812 −54.702 −41.326 1.00 203.87 ATOM 2642 CB LEU E 69 23.221 −56.482 −40.964 1.00 197.47 ATOM 2643 CG LEU E 69 22.717 −57.892 −40.659 1.00 198.25 ATOM 2644 CD1 LEU E 69 22.876 −58.819 −41.846 1.00 200.16 ATOM 2645 CD2 LEU E 69 23.427 −58.448 −39.427 1.00 195.84 ATOM 2646 N GLU E 70 20.497 −56.034 −43.148 1.00 203.27 ATOM 2647 CA GLU E 70 19.066 −55.781 −43.391 1.00 203.50 ATOM 2648 C GLU E 70 18.075 −56.850 −42.877 1.00 202.93 ATOM 2649 O GLU E 70 16.884 −56.576 −42.688 1.00 201.71 ATOM 2650 CB GLU E 70 18.859 −55.528 −44.894 1.00 209.35 ATOM 2651 CG GLU E 70 19.653 −54.328 −45.388 1.00 222.87 ATOM 2652 CD GLU E 70 19.688 −54.070 −46.884 1.00 248.25 ATOM 2653 OE1 GLU E 70 19.376 −52.929 −47.300 1.00 235.06 ATOM 2654 OE2 GLU E 70 20.192 −54.950 −47.619 1.00 247.85 ATOM 2655 N SER E 71 18.567 −58.061 −42.694 1.00 196.85 ATOM 2656 CA SER E 71 17.792 −59.198 −42.245 1.00 193.81 ATOM 2657 C SER E 71 18.796 −60.204 −41.732 1.00 196.83 ATOM 2658 O SER E 71 19.961 −60.186 −42.140 1.00 198.66 ATOM 2659 CB SER E 71 17.014 −59.808 −43.412 1.00 198.99 ATOM 2660 OG SER E 71 16.265 −60.945 −43.011 1.00 205.64 ATOM 2661 N LEU E 72 18.342 −61.086 −40.846 1.00 189.69 ATOM 2662 CA LEU E 72 19.152 −62.176 −40.325 1.00 186.70 ATOM 2663 C LEU E 72 18.751 −63.499 −40.952 1.00 191.05 ATOM 2664 O LEU E 72 19.353 −64.507 −40.611 1.00 189.12 ATOM 2665 CB LEU E 72 19.008 −62.286 −38.803 1.00 182.94 ATOM 2666 CG LEU E 72 19.239 −61.017 −38.003 1.00 186.91 ATOM 2667 CD1 LEU E 72 18.939 −61.238 −36.530 1.00 183.34 ATOM 2668 CD2 LEU E 72 20.637 −60.505 −38.192 1.00 189.87 ATOM 2669 N LYS E 73 17.752 −63.516 −41.856 1.00 190.50 ATOM 2670 CA LYS E 73 17.232 −64.736 −42.475 1.00 191.52 ATOM 2671 C LYS E 73 18.271 −65.564 −43.237 1.00 198.31 ATOM 2672 O LYS E 73 18.098 −66.777 −43.357 1.00 197.77 ATOM 2673 CB LYS E 73 16.017 −64.426 −43.366 1.00 197.26 ATOM 2674 CG LYS E 73 16.392 −63.931 −44.769 1.00 221.92 ATOM 2675 CD LYS E 73 15.232 −63.426 −45.623 1.00 234.55 ATOM 2676 CE LYS E 73 14.275 −64.451 −46.195 1.00 246.97 ATOM 2677 NZ LYS E 73 12.950 −63.850 −46.530 1.00 257.96 ATOM 2678 N ASP E 74 19.303 −64.898 −43.800 1.00 197.32 ATOM 2679 CA ASP E 74 20.367 −65.557 −44.546 1.00 199.31 ATOM 2680 C ASP E 74 21.532 −65.804 −43.624 1.00 201.40 ATOM 2681 O ASP E 74 22.249 −66.782 −43.802 1.00 201.86 ATOM 2682 CB ASP E 74 20.838 −64.722 −45.750 1.00 205.61 ATOM 2683 CG ASP E 74 19.744 −64.026 −46.553 1.00 219.18 ATOM 2684 OD2 ASP E 74 19.520 −64.413 −47.726 1.00 229.32 ATOM 2685 OD1 ASP E 74 19.142 −63.061 −46.024 1.00 218.24 ATOM 2686 N LEU E 75 21.749 −64.919 −42.654 1.00 195.55 ATOM 2687 CA LEU E 75 22.846 −65.113 −41.729 1.00 193.35 ATOM 2688 C LEU E 75 22.624 −66.337 −40.804 1.00 197.60 ATOM 2689 O LEU E 75 23.466 −67.243 −40.790 1.00 197.65 ATOM 2690 CB LEU E 75 23.060 −63.838 −40.936 1.00 191.34 ATOM 2691 CG LEU E 75 24.434 −63.582 −40.354 1.00 194.18 ATOM 2692 CD1 LEU E 75 25.527 −63.642 −41.409 1.00 196.90 ATOM 2693 CD2 LEU E 75 24.434 −62.223 −39.680 1.00 196.18 ATOM 2694 N PHE E 76 21.478 −66.394 −40.071 1.00 192.83 ATOM 2695 CA PHE E 76 21.190 −67.490 −39.108 1.00 189.03 ATOM 2696 C PHE E 76 19.865 −68.177 −39.398 1.00 195.86 ATOM 2697 O PHE E 76 18.947 −68.154 −38.561 1.00 192.12 ATOM 2698 CB PHE E 76 21.197 −66.950 −37.683 1.00 186.33 ATOM 2699 CG PHE E 76 22.432 −66.170 −37.334 1.00 186.59 ATOM 2700 CD2 PHE E 76 22.348 −64.826 −37.010 1.00 187.73 ATOM 2701 CD1 PHE E 76 23.687 −66.779 −37.339 1.00 188.47 ATOM 2702 CE2 PHE E 76 23.489 −64.109 −36.666 1.00 190.53 ATOM 2703 CE1 PHE E 76 24.829 −66.058 −37.012 1.00 189.50 ATOM 2704 CZ PHE E 76 24.718 −64.735 −36.653 1.00 188.83 ATOM 2705 N PRO E 77 19.775 −68.827 −40.586 1.00 198.47 ATOM 2706 CA PRO E 77 18.492 −69.424 −41.004 1.00 199.27 ATOM 2707 C PRO E 77 17.974 −70.569 −40.140 1.00 201.11 ATOM 2708 O PRO E 77 16.758 −70.802 −40.092 1.00 200.33 ATOM 2709 CB PRO E 77 18.775 −69.889 −42.440 1.00 204.88 ATOM 2710 CG PRO E 77 20.282 −70.074 −42.503 1.00 210.19 ATOM 2711 CD PRO E 77 20.831 −69.030 −41.610 1.00 203.64 ATOM 2712 N ASN E 78 18.910 −71.290 −39.481 1.00 195.34 ATOM 2713 CA ASN E 78 18.638 −72.493 −38.706 1.00 191.99 ATOM 2714 C ASN E 78 18.737 −72.361 −37.204 1.00 190.82 ATOM 2715 O ASN E 78 18.559 −73.362 −36.505 1.00 189.91 ATOM 2716 CB ASN E 78 19.498 −73.637 −39.228 1.00 191.18 ATOM 2717 CG ASN E 78 19.082 −74.066 −40.605 1.00 207.69 ATOM 2718 OD1 ASN E 78 17.889 −74.265 −40.872 1.00 196.81 ATOM 2719 ND2 ASN E 78 20.044 −74.156 −41.522 1.00 201.87 ATOM 2720 N LEU E 79 19.017 −71.151 −36.698 1.00 183.87 ATOM 2721 CA LEU E 79 19.107 −70.919 −35.259 1.00 179.34 ATOM 2722 C LEU E 79 17.728 −71.173 −34.668 1.00 184.27 ATOM 2723 O LEU E 79 16.773 −70.459 −34.992 1.00 185.10 ATOM 2724 CB LEU E 79 19.606 −69.512 −34.942 1.00 177.52 ATOM 2725 CG LEU E 79 19.636 −69.171 −33.473 1.00 175.99 ATOM 2726 CD1 LEU E 79 20.726 −69.923 −32.752 1.00 175.09 ATOM 2727 CD2 LEU E 79 19.839 −67.746 −33.295 1.00 173.84 ATOM 2728 N THR E 80 17.638 −72.237 −33.842 1.00 179.71 ATOM 2729 CA THR E 80 16.404 −72.811 −33.289 1.00 178.14 ATOM 2730 C THR E 80 16.193 −72.529 −31.816 1.00 178.57 ATOM 2731 O THR E 80 15.050 −72.369 −31.374 1.00 177.86 ATOM 2732 CB THR E 80 16.367 −74.343 −33.593 1.00 187.50 ATOM 2733 OG1 THR E 80 16.520 −74.564 −34.994 1.00 196.24 ATOM 2734 CG2 THR E 80 15.058 −75.005 −33.188 1.00 180.91 ATOM 2735 N VAL E 81 17.281 −72.533 −31.046 1.00 172.91 ATOM 2736 CA VAL E 81 17.224 −72.354 −29.600 1.00 170.72 ATOM 2737 C VAL E 81 18.328 −71.421 −29.126 1.00 178.24 ATOM 2738 O VAL E 81 19.478 −71.492 −29.575 1.00 179.01 ATOM 2739 CB VAL E 81 17.328 −73.717 −28.843 1.00 171.97 ATOM 2740 CG1 VAL E 81 17.314 −73.535 −27.324 1.00 169.77 ATOM 2741 CG2 VAL E 81 16.240 −74.676 −29.261 1.00 171.64 ATOM 2742 N ILE E 82 17.966 −70.553 −28.201 1.00 175.53 ATOM 2743 CA ILE E 82 18.896 −69.721 −27.458 1.00 175.30 ATOM 2744 C ILE E 82 18.564 −70.134 −26.017 1.00 179.61 ATOM 2745 O ILE E 82 17.454 −69.879 −25.560 1.00 181.02 ATOM 2746 CB ILE E 82 18.712 −68.205 −27.703 1.00 178.35 ATOM 2747 CG1 ILE E 82 18.911 −67.828 −29.167 1.00 178.59 ATOM 2748 CG2 ILE E 82 19.665 −67.438 −26.803 1.00 179.79 ATOM 2749 CD1 ILE E 82 18.393 −66.488 −29.491 1.00 175.19 ATOM 2750 N ARG E 83 19.471 −70.817 −25.334 1.00 174.24 ATOM 2751 CA ARG E 83 19.186 −71.349 −24.007 1.00 173.20 ATOM 2752 C ARG E 83 19.122 −70.332 −22.867 1.00 176.94 ATOM 2753 O ARG E 83 18.357 −70.514 −21.909 1.00 175.18 ATOM 2754 CB ARG E 83 20.118 −72.517 −23.688 1.00 173.12 ATOM 2755 CG ARG E 83 19.967 −73.668 −24.667 1.00 176.74 ATOM 2756 CD ARG E 83 20.701 −74.889 −24.193 1.00 184.58 ATOM 2757 NE ARG E 83 19.973 −75.623 −23.159 1.00 192.85 ATOM 2758 CZ ARG E 83 19.038 −76.534 −23.409 1.00 202.35 ATOM 2759 NH1 ARG E 83 18.688 −76.811 −24.659 1.00 180.49 ATOM 2760 NH2 ARG E 83 18.437 −77.167 −22.410 1.00 190.84 ATOM 2761 N GLY E 84 19.909 −69.279 −22.967 1.00 174.94 ATOM 2762 CA GLY E 84 19.871 −68.250 −21.946 1.00 175.76 ATOM 2763 C GLY E 84 20.458 −68.675 −20.620 1.00 181.73 ATOM 2764 O GLY E 84 19.985 −68.214 −19.582 1.00 181.69 ATOM 2765 N SER E 85 21.501 −69.542 −20.637 1.00 180.07 ATOM 2766 CA SER E 85 22.184 −70.025 −19.417 1.00 180.98 ATOM 2767 C SER E 85 22.790 −68.870 −18.646 1.00 186.48 ATOM 2768 O SER E 85 22.747 −68.870 −17.414 1.00 187.61 ATOM 2769 CB SER E 85 23.254 −71.054 −19.754 1.00 186.06 ATOM 2770 OG SER E 85 22.641 −72.211 −20.291 1.00 197.31 ATOM 2771 N ARG E 86 23.396 −67.918 −19.382 1.00 181.98 ATOM 2772 CA ARG E 86 23.864 −66.622 −18.915 1.00 181.47 ATOM 2773 C ARG E 86 23.139 −65.624 −19.804 1.00 181.77 ATOM 2774 O ARG E 86 22.841 −65.916 −20.970 1.00 181.26 ATOM 2775 CB ARG E 86 25.378 −66.462 −19.018 1.00 183.44 ATOM 2776 CG ARG E 86 26.120 −67.009 −17.823 1.00 195.04 ATOM 2777 CD ARG E 86 27.040 −68.131 −18.228 1.00 208.09 ATOM 2778 NE ARG E 86 26.574 −69.397 −17.659 1.00 217.74 ATOM 2779 CZ ARG E 86 27.244 −70.542 −17.700 1.00 222.22 ATOM 2780 NH1 ARG E 86 28.433 −70.603 −18.290 1.00 209.39 ATOM 2781 NH2 ARG E 86 26.736 −71.633 −17.141 1.00 196.49 ATOM 2782 N LEU E 87 22.799 −64.474 −19.240 1.00 175.98 ATOM 2783 CA LEU E 87 22.026 −63.474 −19.958 1.00 175.19 ATOM 2784 C LEU E 87 22.713 −62.127 −19.992 1.00 178.90 ATOM 2785 O LEU E 87 23.607 −61.852 −19.188 1.00 179.89 ATOM 2786 CB LEU E 87 20.656 −63.311 −19.288 1.00 174.99 ATOM 2787 CG LEU E 87 19.785 −64.536 −19.139 1.00 178.18 ATOM 2788 CD1 LEU E 87 18.644 −64.247 −18.198 1.00 179.32 ATOM 2789 CD2 LEU E 87 19.245 −64.983 −20.461 1.00 179.66 ATOM 2790 N PHE E 88 22.255 −61.266 −20.900 1.00 173.38 ATOM 2791 CA PHE E 88 22.765 −59.921 −21.019 1.00 173.37 ATOM 2792 C PHE E 88 21.701 −59.093 −20.345 1.00 178.78 ATOM 2793 O PHE E 88 20.647 −58.878 −20.939 1.00 178.53 ATOM 2794 CB PHE E 88 22.936 −59.554 −22.499 1.00 174.47 ATOM 2795 CG PHE E 88 23.702 −58.286 −22.706 1.00 176.61 ATOM 2796 CD1 PHE E 88 25.086 −58.292 −22.733 1.00 179.18 ATOM 2797 CD2 PHE E 88 23.043 −57.085 −22.881 1.00 180.57 ATOM 2798 CE1 PHE E 88 25.795 −57.120 −22.907 1.00 183.05 ATOM 2799 CE2 PHE E 88 23.754 −55.906 −23.047 1.00 186.38 ATOM 2800 CZ PHE E 88 25.128 −55.931 −23.071 1.00 185.07 ATOM 2801 N PHE E 89 21.931 −58.707 −19.078 1.00 176.57 ATOM 2802 CA PHE E 89 20.924 −57.998 −18.279 1.00 178.27 ATOM 2803 C PHE E 89 19.526 −58.612 −18.475 1.00 180.58 ATOM 2804 O PHE E 89 18.718 −57.987 −19.144 1.00 180.58 ATOM 2805 CB PHE E 89 20.806 −56.520 −18.691 1.00 183.00 ATOM 2806 CG PHE E 89 20.092 −55.627 −17.699 1.00 187.96 ATOM 2807 CD1 PHE E 89 20.635 −54.403 −17.331 1.00 194.81 ATOM 2808 CD2 PHE E 89 18.878 −56.017 −17.124 1.00 190.94 ATOM 2809 CE1 PHE E 89 19.992 −53.586 −16.401 1.00 198.82 ATOM 2810 CE2 PHE E 89 18.229 −55.202 −16.199 1.00 197.17 ATOM 2811 CZ PHE E 89 18.788 −53.986 −15.846 1.00 198.39 ATOM 2812 N ASN E 90 19.216 −59.801 −17.925 1.00 175.34 ATOM 2813 CA ASN E 90 17.913 −60.481 −18.103 1.00 173.68 ATOM 2814 C ASN E 90 17.481 −60.831 −19.540 1.00 172.91 ATOM 2815 O ASN E 90 16.408 −61.416 −19.688 1.00 172.46 ATOM 2816 CB ASN E 90 16.763 −59.806 −17.337 1.00 180.08 ATOM 2817 CG ASN E 90 17.065 −59.588 −15.884 1.00 232.02 ATOM 2818 OD1 ASN E 90 18.013 −58.871 −15.525 1.00 231.93 ATOM 2819 ND2 ASN E 90 16.267 −60.205 −15.017 1.00 231.15 ATOM 2820 N TYR E 91 18.282 −60.508 −20.580 1.00 165.62 ATOM 2821 CA TYR E 91 17.895 −60.795 −21.958 1.00 163.02 ATOM 2822 C TYR E 91 18.701 −61.872 −22.614 1.00 163.85 ATOM 2823 O TYR E 91 19.923 −61.922 −22.471 1.00 162.85 ATOM 2824 CB TYR E 91 17.922 −59.542 −22.829 1.00 165.33 ATOM 2825 CG TYR E 91 17.140 −58.402 −22.241 1.00 168.43 ATOM 2826 CD2 TYR E 91 17.783 −57.296 −21.712 1.00 171.71 ATOM 2827 CD1 TYR E 91 15.750 −58.407 −22.251 1.00 170.39 ATOM 2828 CE2 TYR E 91 17.069 −56.257 −21.114 1.00 175.19 ATOM 2829 CE1 TYR E 91 15.019 −57.367 −21.666 1.00 173.69 ATOM 2830 CZ TYR E 91 15.686 −56.302 −21.074 1.00 180.28 ATOM 2831 OH TYR E 91 14.974 −55.268 −20.511 1.00 178.14 ATOM 2832 N ALA E 92 18.012 −62.735 −23.346 1.00 160.00 ATOM 2833 CA ALA E 92 18.656 −63.791 −24.115 1.00 159.46 ATOM 2834 C ALA E 92 18.820 −63.345 −25.582 1.00 165.58 ATOM 2835 O ALA E 92 19.590 −63.960 −26.326 1.00 166.58 ATOM 2836 CB ALA E 92 17.853 −65.072 −24.030 1.00 158.87 ATOM 2837 N LEU E 93 18.082 −62.295 −26.001 1.00 161.68 ATOM 2838 CA LEU E 93 18.144 −61.760 −27.357 1.00 162.51 ATOM 2839 C LEU E 93 18.133 −60.237 −27.315 1.00 170.84 ATOM 2840 O LEU E 93 17.174 −59.638 −26.807 1.00 174.02 ATOM 2841 CB LEU E 93 16.978 −62.282 −28.218 1.00 161.93 ATOM 2842 CG LEU E 93 16.945 −61.780 −29.667 1.00 167.00 ATOM 2843 CD1 LEU E 93 18.178 −62.252 −30.433 1.00 166.62 ATOM 2844 CD2 LEU E 93 15.682 −62.190 −30.377 1.00 168.02 ATOM 2845 N VAL E 94 19.194 −59.609 −27.852 1.00 165.99 ATOM 2846 CA VAL E 94 19.338 −58.150 −27.862 1.00 166.45 ATOM 2847 C VAL E 94 19.626 −57.642 −29.283 1.00 171.68 ATOM 2848 O VAL E 94 20.628 −58.017 −29.896 1.00 171.86 ATOM 2849 CB VAL E 94 20.401 −57.679 −26.832 1.00 169.12 ATOM 2850 CG1 VAL E 94 20.533 −56.164 −26.788 1.00 170.73 ATOM 2851 CG2 VAL E 94 20.088 −58.204 −25.447 1.00 167.28 ATOM 2852 N ILE E 95 18.727 −56.791 −29.796 1.00 168.62 ATOM 2853 CA ILE E 95 18.814 −56.130 −31.102 1.00 169.60 ATOM 2854 C ILE E 95 18.740 −54.634 −30.781 1.00 172.68 ATOM 2855 O ILE E 95 17.658 −54.102 −30.487 1.00 170.08 ATOM 2856 CB ILE E 95 17.656 −56.578 −32.026 1.00 172.90 ATOM 2857 CG1 ILE E 95 17.586 −58.109 −32.182 1.00 170.00 ATOM 2858 CG2 ILE E 95 17.740 −55.886 −33.367 1.00 177.83 ATOM 2859 CD1 ILE E 95 18.672 −58.757 −33.017 1.00 171.24 ATOM 2860 N PHE E 96 19.900 −53.974 −30.795 1.00 171.67 ATOM 2861 CA PHE E 96 20.011 −52.592 −30.371 1.00 174.46 ATOM 2862 C PHE E 96 20.809 −51.725 −31.324 1.00 180.83 ATOM 2863 O PHE E 96 21.924 −52.066 −31.693 1.00 177.59 ATOM 2864 CB PHE E 96 20.632 −52.563 −28.970 1.00 175.25 ATOM 2865 CG PHE E 96 20.729 −51.211 −28.313 1.00 179.66 ATOM 2866 CD1 PHE E 96 19.592 −50.480 −28.021 1.00 183.82 ATOM 2867 CD2 PHE E 96 21.952 −50.711 −27.899 1.00 184.28 ATOM 2868 CE1 PHE E 96 19.682 −49.246 −27.380 1.00 187.85 ATOM 2869 CE2 PHE E 96 22.045 −49.471 −27.262 1.00 190.09 ATOM 2870 CZ PHE E 96 20.908 −48.749 −27.001 1.00 189.46 ATOM 2871 N GLU E 97 20.226 −50.592 −31.724 1.00 182.89 ATOM 2872 CA GLU E 97 20.852 −49.641 −32.630 1.00 186.67 ATOM 2873 C GLU E 97 21.392 −50.336 −33.865 1.00 194.47 ATOM 2874 O GLU E 97 22.528 −50.122 −34.247 1.00 194.76 ATOM 2875 CB GLU E 97 21.888 −48.772 −31.901 1.00 188.95 ATOM 2876 CG GLU E 97 21.240 −47.843 −30.888 1.00 199.31 ATOM 2877 CD GLU E 97 22.080 −46.764 −30.229 1.00 219.81 ATOM 2878 OE1 GLU E 97 21.449 −45.829 −29.683 1.00 197.61 ATOM 2879 OE2 GLU E 97 23.329 −46.887 −30.164 1.00 218.54 ATOM 2880 N MET E 98 20.569 −51.229 −34.439 1.00 194.51 ATOM 2881 CA MET E 98 20.806 −51.944 −35.696 1.00 196.90 ATOM 2882 C MET E 98 20.191 −51.103 −36.823 1.00 206.23 ATOM 2883 O MET E 98 19.078 −51.352 −37.325 1.00 206.42 ATOM 2884 CB MET E 98 20.240 −53.366 −35.657 1.00 196.87 ATOM 2885 CG MET E 98 21.007 −54.269 −34.743 1.00 198.65 ATOM 2886 SD MET E 98 22.630 −54.733 −35.365 1.00 205.73 ATOM 2887 CE MET E 98 22.181 −55.901 −36.671 1.00 202.87 ATOM 2888 N VAL E 99 20.910 −50.021 −37.132 1.00 206.79 ATOM 2889 CA VAL E 99 20.515 −49.079 −38.142 1.00 211.29 ATOM 2890 C VAL E 99 20.782 −49.876 −39.370 1.00 217.99 ATOM 2891 O VAL E 99 21.882 −50.409 −39.537 1.00 218.07 ATOM 2892 CB VAL E 99 21.290 −47.745 −38.181 1.00 218.69 ATOM 2893 CG1 VAL E 99 20.461 −46.717 −38.946 1.00 223.17 ATOM 2894 CG2 VAL E 99 21.592 −47.221 −36.775 1.00 216.83 ATOM 2895 N HIS E 100 19.718 −50.108 −40.106 1.00 216.01 ATOM 2896 CA HIS E 100 19.564 −50.833 −41.368 1.00 217.10 ATOM 2897 C HIS E 100 18.745 −52.090 −41.285 1.00 216.04 ATOM 2898 O HIS E 100 18.309 −52.549 −42.334 1.00 217.47 ATOM 2899 CB HIS E 100 20.852 −51.066 −42.197 1.00 219.75 ATOM 2900 CG HIS E 100 21.659 −49.832 −42.452 1.00 226.79 ATOM 2901 ND1 HIS E 100 23.034 −49.842 −42.326 1.00 228.43 ATOM 2902 CD2 HIS E 100 21.258 −48.577 −42.751 1.00 232.39 ATOM 2903 CE1 HIS E 100 23.430 −48.612 −42.586 1.00 231.74 ATOM 2904 NE2 HIS E 100 22.398 −47.820 −42.870 1.00 234.63 ATOM 2905 N LEU E 101 18.512 −52.653 −40.089 1.00 206.81 ATOM 2906 CA LEU E 101 17.755 −53.901 −40.001 1.00 203.12 ATOM 2907 C LEU E 101 16.294 −53.662 −40.298 1.00 208.45 ATOM 2908 O LEU E 101 15.678 −52.787 −39.693 1.00 207.91 ATOM 2909 CB LEU E 101 17.974 −54.601 −38.656 1.00 198.42 ATOM 2910 CG LEU E 101 17.659 −56.100 −38.590 1.00 199.13 ATOM 2911 CD1 LEU E 101 18.736 −56.937 −39.264 1.00 198.64 ATOM 2912 CD2 LEU E 101 17.517 −56.548 −37.162 1.00 197.61 ATOM 2913 N LYS E 102 15.780 −54.378 −41.303 1.00 207.57 ATOM 2914 CA LYS E 102 14.408 −54.235 −41.788 1.00 210.19 ATOM 2915 C LYS E 102 13.472 −55.304 −41.218 1.00 214.61 ATOM 2916 O LYS E 102 12.260 −55.080 −41.117 1.00 214.77 ATOM 2917 CB LYS E 102 14.394 −54.215 −43.328 1.00 215.40 ATOM 2918 CG LYS E 102 15.008 −52.933 −43.887 1.00 224.14 ATOM 2919 CD LYS E 102 15.428 −52.992 −45.340 1.00 233.32 ATOM 2920 CE LYS E 102 15.833 −51.609 −45.824 1.00 239.02 ATOM 2921 NZ LYS E 102 16.816 −51.659 −46.942 1.00 243.77 ATOM 2922 N GLU E 103 14.037 −56.461 −40.840 1.00 210.55 ATOM 2923 CA GLU E 103 13.296 −57.581 −40.254 1.00 208.24 ATOM 2924 C GLU E 103 14.282 −58.425 −39.483 1.00 208.90 ATOM 2925 O GLU E 103 15.473 −58.372 −39.778 1.00 209.79 ATOM 2926 CB GLU E 103 12.632 −58.438 −41.351 1.00 211.49 ATOM 2927 CG GLU E 103 13.632 −58.996 −42.352 1.00 228.95 ATOM 2928 CD GLU E 103 13.073 −59.618 −43.616 1.00 269.43 ATOM 2929 OE1 GLU E 103 11.993 −59.192 −44.092 1.00 274.44 ATOM 2930 OE2 GLU E 103 13.766 −60.502 −44.168 1.00 269.87 ATOM 2931 N LEU E 104 13.803 −59.221 −38.517 1.00 201.53 ATOM 2932 CA LEU E 104 14.665 −60.178 −37.814 1.00 197.58 ATOM 2933 C LEU E 104 14.918 −61.343 −38.743 1.00 199.70 ATOM 2934 O LEU E 104 16.055 −61.662 −39.034 1.00 199.52 ATOM 2935 CB LEU E 104 14.049 −60.711 −36.507 1.00 194.78 ATOM 2936 CG LEU E 104 13.860 −59.717 −35.371 1.00 200.02 ATOM 2937 CD1 LEU E 104 13.429 −60.413 −34.097 1.00 197.75 ATOM 2938 CD2 LEU E 104 15.113 −58.948 −35.103 1.00 203.95 ATOM 2939 N GLY E 105 13.853 −61.991 −39.172 1.00 195.60 ATOM 2940 CA GLY E 105 13.947 −63.116 −40.085 1.00 196.11 ATOM 2941 C GLY E 105 14.530 −64.395 −39.530 1.00 197.63 ATOM 2942 O GLY E 105 14.964 −65.239 −40.310 1.00 197.55 ATOM 2943 N LEU E 106 14.530 −64.571 −38.194 1.00 192.36 ATOM 2944 CA LEU E 106 15.029 −65.789 −37.529 1.00 189.48 ATOM 2945 C LEU E 106 13.901 −66.807 −37.558 1.00 193.82 ATOM 2946 O LEU E 106 13.374 −67.171 −36.517 1.00 190.71 ATOM 2947 CB LEU E 106 15.482 −65.468 −36.080 1.00 186.35 ATOM 2948 CG LEU E 106 16.663 −64.487 −35.962 1.00 190.30 ATOM 2949 CD1 LEU E 106 16.848 −63.990 −34.546 1.00 187.88 ATOM 2950 CD2 LEU E 106 17.949 −65.087 −36.505 1.00 191.97 ATOM 2951 N TYR E 107 13.519 −67.251 −38.767 1.00 194.71 ATOM 2952 CA TYR E 107 12.353 −68.115 −39.008 1.00 195.93 ATOM 2953 C TYR E 107 12.354 −69.510 −38.410 1.00 196.21 ATOM 2954 O TYR E 107 11.284 −70.158 −38.364 1.00 195.35 ATOM 2955 CB TYR E 107 11.925 −68.124 −40.478 1.00 201.82 ATOM 2956 CG TYR E 107 12.935 −68.753 −41.412 1.00 206.44 ATOM 2957 CD1 TYR E 107 12.830 −70.088 −41.788 1.00 208.80 ATOM 2958 CD2 TYR E 107 13.981 −68.002 −41.948 1.00 209.16 ATOM 2959 CE1 TYR E 107 13.755 −70.665 −42.654 1.00 211.84 ATOM 2960 CE2 TYR E 107 14.910 −68.569 −42.810 1.00 212.05 ATOM 2961 CZ TYR E 107 14.785 −69.895 −43.174 1.00 219.83 ATOM 2962 OH TYR E 107 15.702 −70.428 −44.045 1.00 222.64 ATOM 2963 N ASN E 108 13.545 −69.956 −37.929 1.00 189.14 ATOM 2964 CA ASN E 108 13.691 −71.233 −37.241 1.00 185.35 ATOM 2965 C ASN E 108 13.776 −71.097 −35.736 1.00 182.34 ATOM 2966 O ASN E 108 13.872 −72.123 −35.058 1.00 179.59 ATOM 2967 CB ASN E 108 14.844 −72.058 −37.790 1.00 185.83 ATOM 2968 CG ASN E 108 14.423 −72.962 −38.914 1.00 214.49 ATOM 2969 OD1 ASN E 108 13.673 −72.570 −39.812 1.00 215.20 ATOM 2970 ND2 ASN E 108 14.962 −74.174 −38.920 1.00 206.12 ATOM 2971 N LEU E 109 13.707 −69.858 −35.194 1.00 176.36 ATOM 2972 CA LEU E 109 13.800 −69.663 −33.744 1.00 172.95 ATOM 2973 C LEU E 109 12.518 −70.066 −33.026 1.00 175.91 ATOM 2974 O LEU E 109 11.498 −69.393 −33.127 1.00 174.85 ATOM 2975 CB LEU E 109 14.248 −68.250 −33.390 1.00 172.61 ATOM 2976 CG LEU E 109 14.420 −67.956 −31.908 1.00 174.80 ATOM 2977 CD1 LEU E 109 15.609 −68.722 −31.319 1.00 173.54 ATOM 2978 CD2 LEU E 109 14.573 −66.472 −31.671 1.00 177.15 ATOM 2979 N MET E 110 12.585 −71.181 −32.307 1.00 173.32 ATOM 2980 CA MET E 110 11.441 −71.800 −31.662 1.00 173.48 ATOM 2981 C MET E 110 11.323 −71.568 −30.189 1.00 177.79 ATOM 2982 O MET E 110 10.209 −71.554 −29.638 1.00 179.61 ATOM 2983 CB MET E 110 11.490 −73.304 −31.926 1.00 175.77 ATOM 2984 CG MET E 110 11.299 −73.659 −33.372 1.00 182.02 ATOM 2985 SD MET E 110 9.517 −73.431 −33.776 1.00 188.77 ATOM 2986 CE MET E 110 9.444 −71.687 −34.553 1.00 187.26 ATOM 2987 N ASN E 111 12.468 −71.458 −29.539 1.00 171.64 ATOM 2988 CA ASN E 111 12.497 −71.354 −28.106 1.00 169.59 ATOM 2989 C ASN E 111 13.682 −70.542 −27.590 1.00 170.39 ATOM 2990 O ASN E 111 14.800 −70.648 −28.087 1.00 168.69 ATOM 2991 CB ASN E 111 12.502 −72.767 −27.514 1.00 170.07 ATOM 2992 CG ASN E 111 12.403 −72.854 −26.019 1.00 196.20 ATOM 2993 OD1 ASN E 111 13.405 −72.725 −25.292 1.00 195.05 ATOM 2994 ND2 ASN E 111 11.210 −73.094 −25.520 1.00 185.83 ATOM 2995 N ILE E 112 13.411 −69.732 −26.575 1.00 165.18 ATOM 2996 CA ILE E 112 14.374 −68.999 −25.779 1.00 162.75 ATOM 2997 C ILE E 112 14.111 −69.560 −24.381 1.00 169.44 ATOM 2998 O ILE E 112 13.095 −69.258 −23.756 1.00 170.64 ATOM 2999 CB ILE E 112 14.225 −67.489 −25.912 1.00 164.33 ATOM 3000 CG1 ILE E 112 14.631 −67.061 −27.330 1.00 164.68 ATOM 3001 CG2 ILE E 112 15.059 −66.813 −24.850 1.00 162.10 ATOM 3002 CD1 ILE E 112 14.253 −65.647 −27.743 1.00 169.35 ATOM 3003 N THR E 113 14.987 −70.463 −23.949 1.00 166.28 ATOM 3004 CA THR E 113 14.808 −71.267 −22.767 1.00 166.87 ATOM 3005 C THR E 113 14.762 −70.510 −21.483 1.00 175.94 ATOM 3006 O THR E 113 14.000 −70.862 −20.582 1.00 177.47 ATOM 3007 CB THR E 113 15.784 −72.410 −22.767 1.00 173.29 ATOM 3008 OG1 THR E 113 15.910 −72.888 −24.105 1.00 167.88 ATOM 3009 CG2 THR E 113 15.329 −73.553 −21.862 1.00 174.83 ATOM 3010 N ARG E 114 15.571 −69.476 −21.391 1.00 173.86 ATOM 3011 CA ARG E 114 15.610 −68.633 −20.215 1.00 174.08 ATOM 3012 C ARG E 114 15.874 −67.232 −20.685 1.00 178.38 ATOM 3013 O ARG E 114 16.632 −67.043 −21.634 1.00 178.99 ATOM 3014 CB ARG E 114 16.714 −69.129 −19.255 1.00 172.10 ATOM 3015 CG ARG E 114 16.745 −68.406 −17.909 1.00 171.43 ATOM 3016 CD ARG E 114 17.862 −68.895 −17.026 1.00 163.95 ATOM 3017 NE ARG E 114 18.217 −67.895 −16.024 1.00 163.02 ATOM 3018 CZ ARG E 114 19.396 −67.285 −15.950 1.00 181.31 ATOM 3019 NH1 ARG E 114 20.352 −67.570 −16.818 1.00 168.19 ATOM 3020 NH2 ARG E 114 19.625 −66.377 −15.013 1.00 178.46 ATOM 3021 N GLY E 115 15.253 −66.270 −20.029 1.00 174.82 ATOM 3022 CA GLY E 115 15.478 −64.871 −20.348 1.00 175.81 ATOM 3023 C GLY E 115 14.423 −64.268 −21.239 1.00 179.59 ATOM 3024 O GLY E 115 13.497 −64.971 −21.650 1.00 178.34 ATOM 3025 N SER E 116 14.561 −62.946 −21.510 1.00 176.43 ATOM 3026 CA SER E 116 13.653 −62.125 −22.309 1.00 176.41 ATOM 3027 C SER E 116 14.301 −61.511 −23.570 1.00 176.19 ATOM 3028 O SER E 116 15.483 −61.712 −23.837 1.00 175.59 ATOM 3029 CB SER E 116 13.027 −61.039 −21.441 1.00 182.46 ATOM 3030 OG SER E 116 12.419 −61.584 −20.284 1.00 190.11 ATOM 3031 N VAL E 117 13.509 −60.769 −24.338 1.00 170.20 ATOM 3032 CA VAL E 117 13.924 −60.156 −25.585 1.00 169.52 ATOM 3033 C VAL E 117 13.904 −58.654 −25.470 1.00 175.72 ATOM 3034 O VAL E 117 12.898 −58.085 −25.034 1.00 178.51 ATOM 3035 CB VAL E 117 12.985 −60.648 −26.700 1.00 173.28 ATOM 3036 CG1 VAL E 117 13.190 −59.895 −27.989 1.00 174.82 ATOM 3037 CG2 VAL E 117 13.188 −62.119 −26.945 1.00 171.02 ATOM 3038 N ARG E 118 15.007 −58.004 −25.879 1.00 171.58 ATOM 3039 CA ARG E 118 15.095 −56.541 −25.947 1.00 173.70 ATOM 3040 C ARG E 118 15.444 −56.131 −27.347 1.00 179.38 ATOM 3041 O ARG E 118 16.557 −56.386 −27.784 1.00 177.40 ATOM 3042 CB ARG E 118 16.105 −55.940 −24.966 1.00 171.08 ATOM 3043 CG ARG E 118 16.047 −54.416 −24.969 1.00 169.45 ATOM 3044 CD ARG E 118 16.029 −53.908 −23.576 1.00 170.29 ATOM 3045 NE ARG E 118 16.190 −52.467 −23.477 1.00 183.64 ATOM 3046 CZ ARG E 118 15.942 −51.778 −22.366 1.00 211.82 ATOM 3047 NH1 ARG E 118 15.452 −52.388 −21.291 1.00 201.35 ATOM 3048 NH2 ARG E 118 16.116 −50.460 −22.341 1.00 208.19 ATOM 3049 N ILE E 119 14.486 −55.534 −28.055 1.00 179.89 ATOM 3050 CA ILE E 119 14.624 −55.049 −29.429 1.00 182.36 ATOM 3051 C ILE E 119 14.273 −53.561 −29.374 1.00 191.89 ATOM 3052 O ILE E 119 13.097 −53.182 −29.335 1.00 192.31 ATOM 3053 CB ILE E 119 13.715 −55.831 −30.393 1.00 184.83 ATOM 3054 CG1 ILE E 119 14.037 −57.317 −30.394 1.00 180.96 ATOM 3055 CG2 ILE E 119 13.811 −55.247 −31.780 1.00 189.22 ATOM 3056 CD1 ILE E 119 13.064 −58.107 −31.131 1.00 183.23 ATOM 3057 N GLU E 120 15.307 −52.731 −29.366 1.00 192.13 ATOM 3058 CA GLU E 120 15.200 −51.309 −29.108 1.00 196.32 ATOM 3059 C GLU E 120 16.005 −50.410 −30.053 1.00 202.59 ATOM 3060 O GLU E 120 17.167 −50.704 −30.326 1.00 201.57 ATOM 3061 CB GLU E 120 15.674 −51.070 −27.644 1.00 197.26 ATOM 3062 CG GLU E 120 15.817 −49.606 −27.236 1.00 209.96 ATOM 3063 CD GLU E 120 15.394 −49.215 −25.838 1.00 217.56 ATOM 3064 OE1 GLU E 120 15.834 −49.895 −24.887 1.00 198.71 ATOM 3065 OE2 GLU E 120 14.694 −48.184 −25.694 1.00 204.24 ATOM 3066 N LYS E 121 15.413 −49.274 −30.478 1.00 201.45 ATOM 3067 CA LYS E 121 16.082 −48.224 −31.245 1.00 203.74 ATOM 3068 C LYS E 121 16.622 −48.689 −32.584 1.00 208.91 ATOM 3069 O LYS E 121 17.774 −48.422 −32.931 1.00 209.49 ATOM 3070 CB LYS E 121 17.170 −47.526 −30.392 1.00 205.56 ATOM 3071 CG LYS E 121 16.656 −46.597 −29.279 1.00 214.58 ATOM 3072 CD LYS E 121 17.817 −46.067 −28.401 1.00 213.98 ATOM 3073 CE LYS E 121 17.395 −45.545 −27.044 1.00 210.79 ATOM 3074 NZ LYS E 121 16.999 −44.129 −27.109 1.00 225.94 ATOM 3075 N ASN E 122 15.766 −49.385 −33.331 1.00 206.28 ATOM 3076 CA ASN E 122 16.050 −49.913 −34.656 1.00 206.85 ATOM 3077 C ASN E 122 15.175 −49.195 −35.680 1.00 216.44 ATOM 3078 O ASN E 122 14.016 −49.551 −35.915 1.00 215.56 ATOM 3079 CB ASN E 122 15.876 −51.416 −34.689 1.00 200.30 ATOM 3080 CG ASN E 122 16.653 −52.083 −33.599 1.00 216.25 ATOM 3081 OD1 ASN E 122 17.887 −52.114 −33.628 1.00 208.77 ATOM 3082 ND2 ASN E 122 15.953 −52.576 −32.582 1.00 207.65 ATOM 3083 N ASN E 123 15.723 −48.104 −36.213 1.00 218.26 ATOM 3084 CA ASN E 123 15.045 −47.347 −37.230 1.00 223.30 ATOM 3085 C ASN E 123 15.268 −48.194 −38.452 1.00 230.44 ATOM 3086 O ASN E 123 16.395 −48.609 −38.735 1.00 229.46 ATOM 3087 CB ASN E 123 15.600 −45.923 −37.437 1.00 226.78 ATOM 3088 CG ASN E 123 17.049 −45.649 −37.086 1.00 243.17 ATOM 3089 OD1 ASN E 123 17.572 −46.092 −36.048 1.00 230.14 ATOM 3090 ND2 ASN E 123 17.689 −44.804 −37.909 1.00 237.26 ATOM 3091 N GLU E 124 14.162 −48.578 −39.046 1.00 229.88 ATOM 3092 CA GLU E 124 13.929 −49.423 −40.210 1.00 230.93 ATOM 3093 C GLU E 124 13.267 −50.719 −39.802 1.00 232.06 ATOM 3094 O GLU E 124 12.734 −51.382 −40.680 1.00 232.44 ATOM 3095 CB GLU E 124 15.172 −49.726 −41.103 1.00 232.89 ATOM 3096 CG GLU E 124 15.894 −48.536 −41.730 1.00 248.34 ATOM 3097 CD GLU E 124 15.046 −47.443 −42.347 1.00 271.37 ATOM 3098 OE1 GLU E 124 14.103 −47.772 −43.102 1.00 269.99 ATOM 3099 OE2 GLU E 124 15.356 −46.252 −42.111 1.00 266.82 ATOM 3100 N LEU E 125 13.278 −51.100 −38.508 1.00 225.73 ATOM 3101 CA LEU E 125 12.798 −52.429 −38.116 1.00 222.62 ATOM 3102 C LEU E 125 11.310 −52.701 −38.116 1.00 230.85 ATOM 3103 O LEU E 125 10.568 −52.117 −37.321 1.00 231.16 ATOM 3104 CB LEU E 125 13.490 −52.944 −36.834 1.00 218.15 ATOM 3105 CG LEU E 125 13.308 −54.431 −36.414 1.00 217.44 ATOM 3106 CD1 LEU E 125 13.748 −55.394 −37.493 1.00 216.47 ATOM 3107 CD2 LEU E 125 14.100 −54.737 −35.180 1.00 215.38 ATOM 3108 N CYS E 126 10.894 −53.635 −38.991 1.00 230.78 ATOM 3109 CA CYS E 126 9.515 −54.098 −39.128 1.00 232.99 ATOM 3110 C CYS E 126 9.443 −55.597 −38.907 1.00 233.48 ATOM 3111 O CYS E 126 10.410 −56.174 −38.407 1.00 230.94 ATOM 3112 CB CYS E 126 8.924 −53.688 −40.470 1.00 238.89 ATOM 3113 SG CYS E 126 8.660 −51.906 −40.635 1.00 248.77 ATOM 3114 N TYR E 127 8.295 −56.226 −39.223 1.00 229.22 ATOM 3115 CA TYR E 127 8.067 −57.653 −39.001 1.00 225.30 ATOM 3116 C TYR E 127 8.226 −58.030 −37.523 1.00 220.39 ATOM 3117 O TYR E 127 8.716 −59.101 −37.192 1.00 215.83 ATOM 3118 CB TYR E 127 8.887 −58.524 −39.983 1.00 227.50 ATOM 3119 CG TYR E 127 8.292 −58.554 −41.379 1.00 235.61 ATOM 3120 CD1 TYR E 127 8.812 −57.761 −42.404 1.00 242.00 ATOM 3121 CD2 TYR E 127 7.194 −59.360 −41.673 1.00 237.27 ATOM 3122 CE1 TYR E 127 8.248 −57.769 −43.688 1.00 247.85 ATOM 3123 CE2 TYR E 127 6.632 −59.388 −42.953 1.00 242.32 ATOM 3124 CZ TYR E 127 7.156 −58.586 −43.958 1.00 254.90 ATOM 3125 OH TYR E 127 6.590 −58.621 −45.218 1.00 259.42 ATOM 3126 N LEU E 128 7.796 −57.125 −36.642 1.00 215.53 ATOM 3127 CA LEU E 128 7.813 −57.324 −35.201 1.00 211.50 ATOM 3128 C LEU E 128 6.422 −57.612 −34.680 1.00 213.42 ATOM 3129 O LEU E 128 6.263 −58.510 −33.852 1.00 209.21 ATOM 3130 CB LEU E 128 8.376 −56.089 −34.505 1.00 212.12 ATOM 3131 CG LEU E 128 9.840 −55.811 −34.755 1.00 214.78 ATOM 3132 CD1 LEU E 128 10.268 −54.581 −34.011 1.00 215.14 ATOM 3133 CD2 LEU E 128 10.701 −57.011 −34.385 1.00 213.22 ATOM 3134 N ALA E 129 5.411 −56.858 −35.159 1.00 212.72 ATOM 3135 CA ALA E 129 4.017 −57.062 −34.750 1.00 213.13 ATOM 3136 C ALA E 129 3.487 −58.426 −35.225 1.00 214.06 ATOM 3137 O ALA E 129 2.502 −58.934 −34.678 1.00 213.33 ATOM 3138 CB ALA E 129 3.140 −55.951 −35.293 1.00 218.57 ATOM 3139 N THR E 130 4.159 −59.014 −36.232 1.00 208.37 ATOM 3140 CA THR E 130 3.803 −60.280 −36.853 1.00 206.56 ATOM 3141 C THR E 130 4.315 −61.485 −36.115 1.00 210.00 ATOM 3142 O THR E 130 3.968 −62.601 −36.493 1.00 210.58 ATOM 3143 CB THR E 130 4.290 −60.330 −38.303 1.00 200.79 ATOM 3144 OG1 THR E 130 5.685 −60.054 −38.370 1.00 187.94 ATOM 3145 CG2 THR E 130 3.561 −59.372 −39.173 1.00 204.35 ATOM 3146 N ILE E 131 5.179 −61.282 −35.113 1.00 204.44 ATOM 3147 CA ILE E 131 5.778 −62.364 −34.340 1.00 200.07 ATOM 3148 C ILE E 131 4.979 −62.594 −33.065 1.00 201.36 ATOM 3149 O ILE E 131 4.775 −61.659 −32.283 1.00 201.51 ATOM 3150 CB ILE E 131 7.253 −62.038 −33.974 1.00 201.27 ATOM 3151 CG1 ILE E 131 8.144 −61.852 −35.207 1.00 203.09 ATOM 3152 CG2 ILE E 131 7.821 −63.107 −33.052 1.00 198.80 ATOM 3153 CD1 ILE E 131 9.481 −61.142 −34.904 1.00 214.16 ATOM 3154 N ASP E 132 4.596 −63.844 −32.819 1.00 195.30 ATOM 3155 CA ASP E 132 3.991 −64.210 −31.548 1.00 193.98 ATOM 3156 C ASP E 132 5.123 −64.741 −30.655 1.00 192.77 ATOM 3157 O ASP E 132 5.545 −65.914 −30.743 1.00 190.71 ATOM 3158 CB ASP E 132 2.888 −65.262 −31.699 1.00 196.95 ATOM 3159 CG ASP E 132 2.243 −65.693 −30.384 1.00 209.98 ATOM 3160 OD2 ASP E 132 1.429 −66.640 −30.405 1.00 215.84 ATOM 3161 OD1 ASP E 132 2.554 −65.078 −29.326 1.00 210.44 ATOM 3162 N TRP E 133 5.608 −63.865 −29.789 1.00 186.19 ATOM 3163 CA TRP E 133 6.683 −64.215 −28.892 1.00 182.22 ATOM 3164 C TRP E 133 6.263 −65.219 −27.804 1.00 184.18 ATOM 3165 O TRP E 133 7.115 −65.921 −27.272 1.00 181.52 ATOM 3166 CB TRP E 133 7.278 −62.940 −28.300 1.00 181.16 ATOM 3167 CG TRP E 133 8.058 −62.099 −29.277 1.00 183.02 ATOM 3168 CD1 TRP E 133 7.684 −60.898 −29.804 1.00 188.73 ATOM 3169 CD2 TRP E 133 9.372 −62.372 −29.794 1.00 181.53 ATOM 3170 NE1 TRP E 133 8.678 −60.408 −30.619 1.00 188.68 ATOM 3171 CE2 TRP E 133 9.730 −61.289 −30.623 1.00 187.41 ATOM 3172 CE3 TRP E 133 10.273 −63.442 −29.658 1.00 180.46 ATOM 3173 CZ2 TRP E 133 10.943 −61.248 −31.319 1.00 186.25 ATOM 3174 CZ3 TRP E 133 11.485 −63.388 −30.330 1.00 181.59 ATOM 3175 CH2 TRP E 133 11.810 −62.300 −31.147 1.00 184.10 ATOM 3176 N SER E 134 4.962 −65.324 −27.500 1.00 183.16 ATOM 3177 CA SER E 134 4.473 −66.273 −26.490 1.00 182.84 ATOM 3178 C SER E 134 4.729 −67.708 −26.862 1.00 184.35 ATOM 3179 O SER E 134 4.722 −68.554 −25.981 1.00 182.42 ATOM 3180 CB SER E 134 3.000 −66.049 −26.146 1.00 192.31 ATOM 3181 OG SER E 134 2.111 −66.313 −27.220 1.00 209.64 ATOM 3182 N ARG E 135 5.000 −67.986 −28.144 1.00 182.10 ATOM 3183 CA ARG E 135 5.369 −69.331 −28.604 1.00 181.25 ATOM 3184 C ARG E 135 6.871 −69.627 −28.339 1.00 181.24 ATOM 3185 O ARG E 135 7.318 −70.775 −28.453 1.00 178.24 ATOM 3186 CB ARG E 135 5.131 −69.456 −30.121 1.00 184.72 ATOM 3187 CG ARG E 135 3.672 −69.329 −30.572 1.00 198.02 ATOM 3188 CD ARG E 135 2.824 −70.590 −30.311 1.00 204.52 ATOM 3189 NE ARG E 135 1.629 −70.298 −29.509 1.00 209.86 ATOM 3190 CZ ARG E 135 1.529 −70.509 −28.198 1.00 215.28 ATOM 3191 NH1 ARG E 135 2.537 −71.047 −27.525 1.00 195.63 ATOM 3192 NH2 ARG E 135 0.413 −70.193 −27.552 1.00 198.56 ATOM 3193 N ILE E 136 7.646 −68.571 −28.080 1.00 177.14 ATOM 3194 CA ILE E 136 9.090 −68.640 −27.956 1.00 174.94 ATOM 3195 C ILE E 136 9.593 −68.449 −26.524 1.00 178.02 ATOM 3196 O ILE E 136 10.495 −69.149 −26.103 1.00 177.22 ATOM 3197 CB ILE E 136 9.682 −67.638 −28.968 1.00 179.27 ATOM 3198 CG1 ILE E 136 9.227 −67.984 −30.413 1.00 181.96 ATOM 3199 CG2 ILE E 136 11.198 −67.562 −28.858 1.00 178.03 ATOM 3200 CD1 ILE E 136 9.481 −66.904 −31.460 1.00 194.32 ATOM 3201 N LEU E 137 8.993 −67.544 −25.767 1.00 176.20 ATOM 3202 CA LEU E 137 9.372 −67.269 −24.381 1.00 176.29 ATOM 3203 C LEU E 137 8.233 −67.515 −23.453 1.00 184.73 ATOM 3204 O LEU E 137 7.100 −67.079 −23.727 1.00 186.97 ATOM 3205 CB LEU E 137 9.697 −65.799 −24.201 1.00 177.48 ATOM 3206 CG LEU E 137 10.738 −65.204 −25.046 1.00 182.54 ATOM 3207 CD1 LEU E 137 10.142 −64.149 −25.904 1.00 185.04 ATOM 3208 CD2 LEU E 137 11.747 −64.563 −24.203 1.00 184.43 ATOM 3209 N ASP E 138 8.531 −68.126 −22.311 1.00 182.69 ATOM 3210 CA ASP E 138 7.517 −68.299 −21.285 1.00 185.67 ATOM 3211 C ASP E 138 7.018 −66.927 −20.795 1.00 191.98 ATOM 3212 O ASP E 138 5.802 −66.701 −20.660 1.00 192.05 ATOM 3213 CB ASP E 138 8.106 −69.075 −20.101 1.00 188.08 ATOM 3214 CG ASP E 138 8.138 −70.577 −20.276 1.00 205.56 ATOM 3215 OD1 ASP E 138 7.342 −71.106 −21.105 1.00 208.43 ATOM 3216 OD2 ASP E 138 8.934 −71.239 −19.564 1.00 209.81 ATOM 3217 N SER E 139 7.992 −66.011 −20.551 1.00 190.10 ATOM 3218 CA SER E 139 7.785 −64.640 −20.046 1.00 192.18 ATOM 3219 C SER E 139 7.878 −63.590 −21.128 1.00 196.85 ATOM 3220 O SER E 139 8.983 −63.245 −21.527 1.00 196.63 ATOM 3221 CB SER E 139 8.809 −64.306 −18.962 1.00 194.45 ATOM 3222 OG SER E 139 10.122 −64.604 −19.421 1.00 198.39 ATOM 3223 N VAL E 140 6.738 −63.078 −21.599 1.00 194.15 ATOM 3224 CA VAL E 140 6.760 −62.050 −22.633 1.00 195.56 ATOM 3225 C VAL E 140 6.506 −60.712 −21.983 1.00 204.99 ATOM 3226 O VAL E 140 6.658 −59.652 −22.601 1.00 207.30 ATOM 3227 CB VAL E 140 5.801 −62.314 −23.795 1.00 199.97 ATOM 3228 CG1 VAL E 140 6.143 −63.620 −24.482 1.00 197.15 ATOM 3229 CG2 VAL E 140 4.347 −62.310 −23.333 1.00 202.09 ATOM 3230 N GLU E 141 6.145 −60.774 −20.703 1.00 202.82 ATOM 3231 CA GLU E 141 5.842 −59.645 −19.826 1.00 205.72 ATOM 3232 C GLU E 141 7.107 −58.777 −19.641 1.00 209.35 ATOM 3233 O GLU E 141 7.021 −57.554 −19.529 1.00 210.50 ATOM 3234 CB GLU E 141 5.370 −60.181 −18.456 1.00 207.63 ATOM 3235 CG GLU E 141 4.332 −61.299 −18.508 1.00 219.45 ATOM 3236 CD GLU E 141 4.877 −62.718 −18.508 1.00 249.96 ATOM 3237 OE1 GLU E 141 5.854 −62.986 −17.770 1.00 256.95 ATOM 3238 OE2 GLU E 141 4.298 −63.576 −19.214 1.00 246.57 ATOM 3239 N ASP E 142 8.285 −59.440 −19.650 1.00 203.77 ATOM 3240 CA ASP E 142 9.581 −58.802 −19.472 1.00 203.22 ATOM 3241 C ASP E 142 10.282 −58.370 −20.773 1.00 208.44 ATOM 3242 O ASP E 142 11.367 −57.778 −20.724 1.00 209.59 ATOM 3243 CB ASP E 142 10.465 −59.649 −18.556 1.00 202.08 ATOM 3244 CG ASP E 142 9.856 −59.921 −17.188 1.00 207.25 ATOM 3245 OD1 ASP E 142 9.952 −61.080 −16.715 1.00 205.58 ATOM 3246 OD2 ASP E 142 9.267 −58.982 −16.599 1.00 213.47 ATOM 3247 N ASN E 143 9.646 −58.625 −21.929 1.00 203.51 ATOM 3248 CA ASN E 143 10.155 −58.163 −23.219 1.00 202.44 ATOM 3249 C ASN E 143 10.146 −56.627 −23.250 1.00 207.21 ATOM 3250 O ASN E 143 9.318 −55.986 −22.581 1.00 209.60 ATOM 3251 CB ASN E 143 9.304 −58.704 −24.360 1.00 199.49 ATOM 3252 CG ASN E 143 9.610 −60.109 −24.679 1.00 207.69 ATOM 3253 OD1 ASN E 143 10.479 −60.731 −24.069 1.00 203.81 ATOM 3254 ND2 ASN E 143 8.893 −60.639 −25.636 1.00 197.37 ATOM 3255 N HIS E 144 11.073 −56.051 −24.017 1.00 200.69 ATOM 3256 CA HIS E 144 11.193 −54.623 −24.139 1.00 202.34 ATOM 3257 C HIS E 144 11.454 −54.311 −25.590 1.00 204.85 ATOM 3258 O HIS E 144 12.596 −54.293 −26.053 1.00 202.38 ATOM 3259 CB HIS E 144 12.286 −54.138 −23.204 1.00 203.11 ATOM 3260 CG HIS E 144 12.306 −52.668 −23.028 1.00 210.39 ATOM 3261 ND1 HIS E 144 13.182 −51.887 −23.730 1.00 213.62 ATOM 3262 CD2 HIS E 144 11.591 −51.889 −22.189 1.00 215.28 ATOM 3263 CE1 HIS E 144 12.967 −50.648 −23.316 1.00 216.66 ATOM 3264 NE2 HIS E 144 11.996 −50.600 −22.409 1.00 218.15 ATOM 3265 N ILE E 145 10.360 −54.149 −26.330 1.00 203.74 ATOM 3266 CA ILE E 145 10.375 −53.946 −27.772 1.00 204.97 ATOM 3267 C ILE E 145 9.800 −52.593 −28.075 1.00 215.22 ATOM 3268 O ILE E 145 8.581 −52.436 −28.183 1.00 216.85 ATOM 3269 CB ILE E 145 9.621 −55.093 −28.474 1.00 206.07 ATOM 3270 CG1 ILE E 145 10.041 −56.506 −27.967 1.00 202.34 ATOM 3271 CG2 ILE E 145 9.639 −54.943 −29.993 1.00 207.33 ATOM 3272 CD1 ILE E 145 11.348 −56.912 −27.888 1.00 208.65 ATOM 3273 N VAL E 146 10.692 −51.599 −28.170 1.00 214.80 ATOM 3274 CA VAL E 146 10.333 −50.191 −28.330 1.00 219.35 ATOM 3275 C VAL E 146 11.261 −49.414 −29.266 1.00 225.24 ATOM 3276 O VAL E 146 12.398 −49.818 −29.521 1.00 223.68 ATOM 3277 CB VAL E 146 10.286 −49.495 −26.933 1.00 224.48 ATOM 3278 CG1 VAL E 146 9.263 −50.149 −26.002 1.00 223.63 ATOM 3279 CG2 VAL E 146 11.666 −49.463 −26.281 1.00 222.19 ATOM 3280 N LEU E 147 10.787 −48.244 −29.688 1.00 224.87 ATOM 3281 CA LEU E 147 11.510 −47.300 −30.522 1.00 226.99 ATOM 3282 C LEU E 147 12.042 −47.919 −31.838 1.00 231.64 ATOM 3283 O LEU E 147 13.180 −47.708 −32.235 1.00 230.97 ATOM 3284 CB LEU E 147 12.572 −46.522 −29.697 1.00 226.88 ATOM 3285 CG LEU E 147 12.080 −45.830 −28.397 1.00 232.35 ATOM 3286 CD1 LEU E 147 13.241 −45.442 −27.475 1.00 231.82 ATOM 3287 CD2 LEU E 147 11.183 −44.630 −28.692 1.00 238.45 ATOM 3288 N ASN E 148 11.183 −48.671 −32.522 1.00 229.80 ATOM 3289 CA ASN E 148 11.489 −49.258 −33.827 1.00 230.43 ATOM 3290 C ASN E 148 10.563 −48.648 −34.895 1.00 242.79 ATOM 3291 O ASN E 148 9.583 −47.982 −34.535 1.00 246.23 ATOM 3292 CB ASN E 148 11.333 −50.777 −33.764 1.00 225.00 ATOM 3293 CG ASN E 148 12.157 −51.412 −32.663 1.00 235.07 ATOM 3294 OD1 ASN E 148 13.387 −51.329 −32.649 1.00 224.86 ATOM 3295 ND2 ASN E 148 11.498 −52.065 −31.713 1.00 224.04 ATOM 3296 N LYS E 149 10.849 −48.871 −36.208 1.00 241.61 ATOM 3297 CA LYS E 149 9.963 −48.366 −37.276 1.00 245.96 ATOM 3298 C LYS E 149 8.519 −48.815 −37.010 1.00 253.72 ATOM 3299 O LYS E 149 7.590 −48.055 −37.255 1.00 258.37 ATOM 3300 CB LYS E 149 10.409 −48.819 −38.674 1.00 247.39 ATOM 3301 CG LYS E 149 9.583 −48.171 −39.788 1.00 250.74 ATOM 3302 CD LYS E 149 9.971 −48.599 −41.186 1.00 256.23 ATOM 3303 CE LYS E 149 8.844 −48.268 −42.142 1.00 264.82 ATOM 3304 NZ LYS E 149 8.847 −49.150 −43.342 1.00 271.66 ATOM 3305 N ASP E 150 8.361 −50.015 −36.444 1.00 247.57 ATOM 3306 CA ASP E 150 7.113 −50.668 −36.079 1.00 247.35 ATOM 3307 C ASP E 150 6.169 −49.838 −35.198 1.00 255.74 ATOM 3308 O ASP E 150 4.948 −49.999 −35.294 1.00 256.65 ATOM 3309 CB ASP E 150 7.471 −52.002 −35.426 1.00 243.96 ATOM 3310 CG ASP E 150 6.318 −52.712 −34.778 1.00 251.63 ATOM 3311 OD2 ASP E 150 6.347 −52.879 −33.545 1.00 254.53 ATOM 3312 OD1 ASP E 150 5.393 −53.118 −35.504 1.00 253.62 ATOM 3313 N ASP E 151 6.733 −48.971 −34.345 1.00 254.50 ATOM 3314 CA ASP E 151 5.981 −48.099 −33.442 1.00 257.73 ATOM 3315 C ASP E 151 5.222 −47.015 −34.182 1.00 263.97 ATOM 3316 O ASP E 151 4.195 −46.552 −33.685 1.00 264.91 ATOM 3317 CB ASP E 151 6.942 −47.343 −32.515 1.00 259.50 ATOM 3318 CG ASP E 151 7.599 −48.100 −31.392 1.00 269.11 ATOM 3319 OD1 ASP E 151 7.741 −49.338 −31.506 1.00 265.36 ATOM 3320 OD2 ASP E 151 8.056 −47.445 −30.433 1.00 276.45 ATOM 3321 N ASN E 152 5.795 −46.535 −35.303 1.00 261.70 ATOM 3322 CA ASN E 152 5.346 −45.396 −36.092 1.00 262.46 ATOM 3323 C ASN E 152 4.504 −45.787 −37.319 1.00 266.52 ATOM 3324 O ASN E 152 4.885 −45.520 −38.465 1.00 266.28 ATOM 3325 CB ASN E 152 6.554 −44.496 −36.412 1.00 259.59 ATOM 3326 CG ASN E 152 7.801 −44.838 −35.586 1.00 260.81 ATOM 3327 OD1 ASN E 152 7.820 −44.784 −34.343 1.00 247.20 ATOM 3328 ND2 ASN E 152 8.832 −45.319 −36.247 1.00 254.80 ATOM 3329 N GLU E 153 3.346 −46.450 −37.021 1.00 265.11 ATOM 3330 CA GLU E 153 2.176 −46.966 −37.775 1.00 265.17 ATOM 3331 C GLU E 153 2.306 −47.591 −39.172 1.00 267.34 ATOM 3332 O GLU E 153 1.491 −48.460 −39.515 1.00 267.13 ATOM 3333 CB GLU E 153 0.982 −45.975 −37.720 1.00 267.16 ATOM 3334 CG GLU E 153 −0.379 −46.652 −37.632 1.00 272.02 ATOM 3335 CD GLU E 153 −1.581 −45.758 −37.856 1.00 279.42 ATOM 3336 OE1 GLU E 153 −1.604 −45.027 −38.873 1.00 276.01 ATOM 3337 OE2 GLU E 153 −2.526 −45.831 −37.039 1.00 268.00 ATOM 3338 N GLU E 154 3.296 −47.152 −39.974 1.00 263.84 ATOM 3339 CA GLU E 154 3.413 −47.595 −41.351 1.00 262.91 ATOM 3340 C GLU E 154 4.496 −48.613 −41.739 1.00 261.68 ATOM 3341 O GLU E 154 5.308 −48.390 −42.647 1.00 261.48 ATOM 3342 CB GLU E 154 3.216 −46.432 −42.333 1.00 265.14 ATOM 3343 CG GLU E 154 1.799 −45.881 −42.248 1.00 271.87 ATOM 3344 CD GLU E 154 1.464 −44.804 −43.256 1.00 288.24 ATOM 3345 OE1 GLU E 154 1.140 −45.150 −44.416 1.00 288.58 ATOM 3346 OE2 GLU E 154 1.480 −43.611 −42.876 1.00 286.20 ATOM 3347 N CYS E 155 4.422 −49.776 −41.067 1.00 255.80 ATOM 3348 CA CYS E 155 5.201 −50.946 −41.415 1.00 254.35 ATOM 3349 C CYS E 155 4.222 −51.677 −42.303 1.00 255.43 ATOM 3350 O CYS E 155 3.222 −52.225 −41.812 1.00 253.60 ATOM 3351 CB CYS E 155 5.531 −51.812 −40.205 1.00 249.22 ATOM 3352 SG CYS E 155 7.107 −51.440 −39.393 1.00 249.63 ATOM 3353 N GLY E 156 4.502 −51.705 −43.589 1.00 252.77 ATOM 3354 CA GLY E 156 3.662 −52.429 −44.527 1.00 252.49 ATOM 3355 C GLY E 156 3.930 −53.921 −44.471 1.00 253.45 ATOM 3356 O GLY E 156 4.269 −54.524 −45.494 1.00 254.21 ATOM 3357 N ASP E 157 3.801 −54.532 −43.274 1.00 246.37 ATOM 3358 CA ASP E 157 4.050 −55.960 −43.078 1.00 241.60 ATOM 3359 C ASP E 157 3.095 −56.797 −43.886 1.00 243.77 ATOM 3360 O ASP E 157 1.891 −56.557 −43.852 1.00 244.57 ATOM 3361 CB ASP E 157 3.929 −56.332 −41.605 1.00 240.19 ATOM 3362 CG ASP E 157 5.045 −55.831 −40.694 1.00 255.63 ATOM 3363 OD2 ASP E 157 4.820 −55.758 −39.466 1.00 260.85 ATOM 3364 OD1 ASP E 157 6.161 −55.551 −41.202 1.00 258.38 ATOM 3365 N ILE E 158 3.640 −57.763 −44.638 1.00 238.32 ATOM 3366 CA ILE E 158 2.875 −58.643 −45.528 1.00 239.35 ATOM 3367 C ILE E 158 3.331 −60.080 −45.381 1.00 239.04 ATOM 3368 O ILE E 158 4.521 −60.348 −45.542 1.00 237.44 ATOM 3369 CB ILE E 158 2.915 −58.181 −47.021 1.00 247.07 ATOM 3370 CG1 ILE E 158 4.348 −58.033 −47.609 1.00 246.79 ATOM 3371 CG2 ILE E 158 2.016 −56.981 −47.311 1.00 249.81 ATOM 3372 CD1 ILE E 158 4.634 −58.967 −48.780 1.00 249.78 ATOM 3373 N CYS E 159 2.396 −61.010 −45.093 1.00 233.45 ATOM 3374 CA CYS E 159 2.730 −62.421 −44.837 1.00 247.83 ATOM 3375 C CYS E 159 2.532 −63.412 −46.013 1.00 212.30 ATOM 3376 O CYS E 159 3.112 −64.515 −46.030 1.00 153.50 ATOM 3377 CB CYS E 159 2.054 −62.906 −43.555 1.00 245.20 ATOM 3378 SG CYS E 159 2.641 −62.090 −42.029 1.00 245.62 ATOM 3379 N ASN E 168 −2.106 −67.815 −45.399 1.00 237.72 ATOM 3380 CA ASN E 168 −1.440 −69.088 −45.099 1.00 234.29 ATOM 3381 C ASN E 168 −0.777 −69.160 −43.717 1.00 232.00 ATOM 3382 O ASN E 168 −0.555 −70.265 −43.213 1.00 228.54 ATOM 3383 CB ASN E 168 −0.419 −69.450 −46.186 1.00 236.07 ATOM 3384 CG ASN E 168 −0.946 −70.368 −47.277 1.00 253.02 ATOM 3385 OD1 ASN E 168 −1.740 −71.292 −47.042 1.00 239.72 ATOM 3386 ND2 ASN E 168 −0.460 −70.172 −48.493 1.00 249.53 ATOM 3387 N CYS E 169 −0.438 −68.006 −43.121 1.00 226.85 ATOM 3388 CA CYS E 169 0.208 −67.995 −41.815 1.00 222.25 ATOM 3389 C CYS E 169 −0.788 −68.180 −40.666 1.00 220.36 ATOM 3390 O CYS E 169 −1.925 −67.718 −40.754 1.00 221.65 ATOM 3391 CB CYS E 169 1.076 −66.755 −41.623 1.00 223.06 ATOM 3392 SG CYS E 169 2.448 −66.587 −42.805 1.00 228.60 ATOM 3393 N PRO E 170 −0.367 −68.864 −39.583 1.00 211.04 ATOM 3394 CA PRO E 170 −1.286 −69.097 −38.465 1.00 209.17 ATOM 3395 C PRO E 170 −1.502 −67.857 −37.609 1.00 209.64 ATOM 3396 O PRO E 170 −0.542 −67.237 −37.156 1.00 207.87 ATOM 3397 CB PRO E 170 −0.618 −70.248 −37.704 1.00 207.71 ATOM 3398 CG PRO E 170 0.831 −70.124 −38.013 1.00 210.62 ATOM 3399 CD PRO E 170 0.952 −69.506 −39.359 1.00 209.05 ATOM 3400 N ALA E 171 −2.745 −67.455 −37.440 1.00 205.68 ATOM 3401 CA ALA E 171 −2.960 −66.311 −36.584 1.00 204.94 ATOM 3402 C ALA E 171 −3.107 −66.796 −35.130 1.00 205.85 ATOM 3403 O ALA E 171 −3.464 −67.952 −34.885 1.00 204.01 ATOM 3404 CB ALA E 171 −4.178 −65.523 −37.027 1.00 209.84 ATOM 3405 N THR E 172 −2.745 −65.920 −34.172 1.00 201.52 ATOM 3406 CA THR E 172 −2.858 −66.098 −32.712 1.00 199.77 ATOM 3407 C THR E 172 −3.434 −64.821 −32.139 1.00 210.73 ATOM 3408 O THR E 172 −3.277 −63.777 −32.766 1.00 212.86 ATOM 3409 CB THR E 172 −1.514 −66.265 −32.021 1.00 194.04 ATOM 3410 OG1 THR E 172 −0.722 −65.075 −32.155 1.00 187.31 ATOM 3411 CG2 THR E 172 −0.782 −67.554 −32.396 1.00 187.40 ATOM 3412 N VAL E 173 −4.051 −64.872 −30.944 1.00 211.17 ATOM 3413 CA VAL E 173 −4.671 −63.688 −30.318 1.00 215.85 ATOM 3414 C VAL E 173 −3.775 −63.084 −29.253 1.00 222.92 ATOM 3415 O VAL E 173 −3.596 −63.707 −28.207 1.00 221.69 ATOM 3416 CB VAL E 173 −6.110 −63.989 −29.781 1.00 222.43 ATOM 3417 CG1 VAL E 173 −6.152 −65.242 −28.908 1.00 219.96 ATOM 3418 CG2 VAL E 173 −6.729 −62.787 −29.057 1.00 225.44 ATOM 3419 N ILE E 174 −3.209 −61.883 −29.475 1.00 222.60 ATOM 3420 CA ILE E 174 −2.369 −61.329 −28.408 1.00 221.73 ATOM 3421 C ILE E 174 −3.063 −60.263 −27.577 1.00 229.49 ATOM 3422 O ILE E 174 −3.118 −60.406 −26.354 1.00 228.87 ATOM 3423 CB ILE E 174 −0.869 −61.130 −28.759 1.00 222.48 ATOM 3424 CG1 ILE E 174 −0.182 −62.518 −28.945 1.00 218.87 ATOM 3425 CG2 ILE E 174 −0.105 −60.279 −27.732 1.00 223.62 ATOM 3426 CD1 ILE E 174 −0.163 −63.538 −27.726 1.00 216.93 ATOM 3427 N ASN E 175 −3.666 −59.269 −28.226 1.00 229.53 ATOM 3428 CA ASN E 175 −4.479 −58.269 −27.544 1.00 233.02 ATOM 3429 C ASN E 175 −5.864 −58.935 −27.384 1.00 237.88 ATOM 3430 O ASN E 175 −6.012 −59.861 −26.593 1.00 234.63 ATOM 3431 CB ASN E 175 −4.503 −56.968 −28.370 1.00 237.61 ATOM 3432 CG ASN E 175 −3.158 −56.266 −28.492 1.00 255.94 ATOM 3433 OD1 ASN E 175 −2.084 −56.851 −28.290 1.00 245.41 ATOM 3434 ND2 ASN E 175 −3.189 −54.971 −28.818 1.00 250.90 ATOM 3435 N GLY E 176 −6.838 −58.508 −28.163 1.00 239.62 ATOM 3436 CA GLY E 176 −8.157 −59.127 −28.210 1.00 242.75 ATOM 3437 C GLY E 176 −8.441 −59.672 −29.599 1.00 248.34 ATOM 3438 O GLY E 176 −9.464 −60.327 −29.833 1.00 249.50 ATOM 3439 N GLN E 177 −7.487 −59.446 −30.519 1.00 243.43 ATOM 3440 CA GLN E 177 −7.594 −59.797 −31.929 1.00 243.13 ATOM 3441 C GLN E 177 −6.550 −60.783 −32.427 1.00 240.81 ATOM 3442 O GLN E 177 −5.415 −60.844 −31.926 1.00 235.92 ATOM 3443 CB GLN E 177 −7.626 −58.520 −32.797 1.00 247.86 ATOM 3444 CG GLN E 177 −6.340 −57.704 −32.740 1.00 248.66 ATOM 3445 CD GLN E 177 −6.444 −56.405 −33.468 1.00 251.12 ATOM 3446 OE1 GLN E 177 −7.399 −55.632 −33.299 1.00 249.02 ATOM 3447 NE2 GLN E 177 −5.410 −56.099 −34.225 1.00 238.39 ATOM 3448 N PHE E 178 −6.953 −61.542 −33.447 1.00 236.91 ATOM 3449 CA PHE E 178 −6.072 −62.497 −34.086 1.00 232.37 ATOM 3450 C PHE E 178 −5.169 −61.774 −35.058 1.00 235.27 ATOM 3451 O PHE E 178 −5.616 −60.901 −35.803 1.00 239.30 ATOM 3452 CB PHE E 178 −6.845 −63.667 −34.711 1.00 234.60 ATOM 3453 CG PHE E 178 −7.296 −64.675 −33.671 1.00 234.24 ATOM 3454 CD1 PHE E 178 −8.545 −64.572 −33.074 1.00 239.70 ATOM 3455 CD2 PHE E 178 −6.461 −65.715 −33.273 1.00 232.54 ATOM 3456 CE1 PHE E 178 −8.956 −65.499 −32.108 1.00 239.20 ATOM 3457 CE2 PHE E 178 −6.872 −66.637 −32.300 1.00 233.78 ATOM 3458 CZ PHE E 178 −8.118 −66.524 −31.727 1.00 234.26 ATOM 3459 N VAL E 179 −3.879 −62.088 −34.977 1.00 226.07 ATOM 3460 CA VAL E 179 −2.829 −61.487 −35.780 1.00 224.74 ATOM 3461 C VAL E 179 −2.061 −62.643 −36.440 1.00 228.36 ATOM 3462 O VAL E 179 −1.568 −63.525 −35.733 1.00 225.86 ATOM 3463 CB VAL E 179 −1.883 −60.604 −34.911 1.00 225.05 ATOM 3464 CG1 VAL E 179 −0.966 −59.759 −35.779 1.00 225.44 ATOM 3465 CG2 VAL E 179 −2.643 −59.728 −33.918 1.00 226.47 ATOM 3466 N GLU E 180 −1.973 −62.632 −37.787 1.00 227.03 ATOM 3467 CA GLU E 180 −1.261 −63.594 −38.656 1.00 225.74 ATOM 3468 C GLU E 180 0.230 −63.655 −38.264 1.00 226.04 ATOM 3469 O GLU E 180 0.810 −62.586 −38.045 1.00 226.81 ATOM 3470 CB GLU E 180 −1.363 −63.083 −40.091 1.00 231.18 ATOM 3471 CG GLU E 180 −1.520 −64.166 −41.136 1.00 247.47 ATOM 3472 CD GLU E 180 −1.340 −63.724 −42.580 1.00 282.69 ATOM 3473 OE1 GLU E 180 −1.705 −62.572 −42.913 1.00 283.36 ATOM 3474 OE2 GLU E 180 −0.882 −64.558 −43.394 1.00 283.91 ATOM 3475 N ARG E 181 0.835 −64.834 −38.102 1.00 217.91 ATOM 3476 CA ARG E 181 2.208 −64.829 −37.620 1.00 214.17 ATOM 3477 C ARG E 181 3.252 −65.238 −38.609 1.00 221.62 ATOM 3478 O ARG E 181 3.214 −66.330 −39.154 1.00 220.61 ATOM 3479 CB ARG E 181 2.329 −65.513 −36.273 1.00 207.37 ATOM 3480 CG ARG E 181 1.367 −64.998 −35.192 1.00 206.93 ATOM 3481 CD ARG E 181 1.690 −63.636 −34.617 1.00 201.28 ATOM 3482 NE ARG E 181 0.677 −63.182 −33.662 1.00 202.00 ATOM 3483 CZ ARG E 181 0.775 −62.071 −32.938 1.00 218.95 ATOM 3484 NH1 ARG E 181 1.852 −61.300 −33.035 1.00 206.33 ATOM 3485 NH2 ARG E 181 −0.211 −61.710 −32.127 1.00 207.74 ATOM 3486 N CYS E 182 4.168 −64.320 −38.880 1.00 223.20 ATOM 3487 CA CYS E 182 5.240 −64.510 −39.838 1.00 225.90 ATOM 3488 C CYS E 182 6.495 −63.714 −39.490 1.00 227.43 ATOM 3489 O CYS E 182 6.445 −62.789 −38.681 1.00 225.99 ATOM 3490 CB CYS E 182 4.747 −64.262 −41.266 1.00 232.28 ATOM 3491 SG CYS E 182 4.631 −62.525 −41.761 1.00 241.16 ATOM 3492 N TRP E 183 7.622 −64.127 −40.079 1.00 224.36 ATOM 3493 CA TRP E 183 8.941 −63.543 −39.872 1.00 224.03 ATOM 3494 C TRP E 183 9.344 −62.622 −41.003 1.00 233.48 ATOM 3495 O TRP E 183 10.030 −61.635 −40.753 1.00 233.18 ATOM 3496 CB TRP E 183 9.991 −64.640 −39.724 1.00 220.46 ATOM 3497 CG TRP E 183 9.909 −65.413 −38.441 1.00 218.03 ATOM 3498 CD1 TRP E 183 9.310 −66.630 −38.246 1.00 219.93 ATOM 3499 CD2 TRP E 183 10.486 −65.041 −37.181 1.00 215.13 ATOM 3500 NE1 TRP E 183 9.476 −67.037 −36.938 1.00 216.20 ATOM 3501 CE2 TRP E 183 10.208 −66.086 −36.266 1.00 216.57 ATOM 3502 CE3 TRP E 183 11.203 −63.920 −36.729 1.00 215.81 ATOM 3503 CZ2 TRP E 183 10.640 −66.045 −34.935 1.00 213.10 ATOM 3504 CZ3 TRP E 183 11.640 −63.891 −35.412 1.00 214.32 ATOM 3505 CH2 TRP E 183 11.352 −64.937 −34.530 1.00 212.52 ATOM 3506 N THR E 184 8.990 −62.989 −42.253 1.00 235.29 ATOM 3507 CA THR E 184 9.264 −62.235 −43.489 1.00 239.99 ATOM 3508 C THR E 184 8.097 −62.462 −44.478 1.00 247.12 ATOM 3509 O THR E 184 7.222 −63.294 −44.216 1.00 245.98 ATOM 3510 CB THR E 184 10.559 −62.725 −44.170 1.00 252.25 ATOM 3511 OG1 THR E 184 10.287 −63.955 −44.839 1.00 252.93 ATOM 3512 CG2 THR E 184 11.714 −62.941 −43.208 1.00 248.83 ATOM 3513 N HIS E 185 8.120 −61.786 −45.641 1.00 247.01 ATOM 3514 CA HIS E 185 7.086 −61.987 −46.653 1.00 249.51 ATOM 3515 C HIS E 185 7.050 −63.422 −47.155 1.00 248.27 ATOM 3516 O HIS E 185 5.998 −63.885 −47.583 1.00 249.08 ATOM 3517 CB HIS E 185 7.238 −60.993 −47.809 1.00 255.71 ATOM 3518 CG HIS E 185 8.579 −61.006 −48.478 1.00 260.62 ATOM 3519 ND1 HIS E 185 9.668 −61.682 −47.929 1.00 259.01 ATOM 3520 CD2 HIS E 185 8.970 −60.402 −49.624 1.00 267.23 ATOM 3521 CE1 HIS E 185 10.671 −61.475 −48.765 1.00 261.09 ATOM 3522 NE2 HIS E 185 10.299 −60.710 −49.801 1.00 266.32 ATOM 3523 N SER E 186 8.169 −64.145 −47.045 1.00 240.29 ATOM 3524 CA SER E 186 8.205 −65.514 −47.522 1.00 239.10 ATOM 3525 C SER E 186 8.359 −66.600 −46.441 1.00 236.82 ATOM 3526 O SER E 186 8.456 −67.774 −46.789 1.00 236.41 ATOM 3527 CB SER E 186 9.234 −65.657 −48.638 1.00 244.29 ATOM 3528 OG SER E 186 10.538 −65.397 −48.150 1.00 248.19 ATOM 3529 N HIS E 187 8.344 −66.241 −45.144 1.00 228.38 ATOM 3530 CA HIS E 187 8.467 −67.249 −44.087 1.00 223.73 ATOM 3531 C HIS E 187 7.427 −67.057 −42.980 1.00 223.51 ATOM 3532 O HIS E 187 7.453 −66.046 −42.262 1.00 221.36 ATOM 3533 CB HIS E 187 9.881 −67.259 −43.469 1.00 222.12 ATOM 3534 CG HIS E 187 11.005 −67.607 −44.402 1.00 227.30 ATOM 3535 ND1 HIS E 187 11.314 −68.922 −44.710 1.00 229.11 ATOM 3536 CD2 HIS E 187 11.921 −66.800 −44.989 1.00 230.75 ATOM 3537 CE1 HIS E 187 12.373 −68.868 −45.507 1.00 230.50 ATOM 3538 NE2 HIS E 187 12.767 −67.611 −45.711 1.00 231.93 ATOM 3539 N CYS E 188 6.538 −68.053 −42.806 1.00 218.88 ATOM 3540 CA CYS E 188 5.556 −68.016 −41.716 1.00 216.76 ATOM 3541 C CYS E 188 6.292 −68.373 −40.416 1.00 216.25 ATOM 3542 O CYS E 188 7.421 −68.923 −40.443 1.00 216.32 ATOM 3543 CB CYS E 188 4.388 −68.982 −41.956 1.00 218.21 ATOM 3544 SG CYS E 188 3.184 −68.453 −43.211 1.00 227.18 ATOM 3545 N GLN E 189 5.646 −68.049 −39.275 1.00 208.27 ATOM 3546 CA GLN E 189 6.112 −68.485 −37.972 1.00 203.19 ATOM 3547 C GLN E 189 5.493 −69.844 −37.818 1.00 205.06 ATOM 3548 O GLN E 189 4.287 −70.028 −38.054 1.00 205.15 ATOM 3549 CB GLN E 189 5.643 −67.582 −36.838 1.00 203.17 ATOM 3550 CG GLN E 189 6.157 −68.045 −35.470 1.00 201.08 ATOM 3551 CD GLN E 189 5.718 −67.165 −34.329 1.00 198.08 ATOM 3552 OE1 GLN E 189 5.023 −66.157 −34.534 1.00 186.53 ATOM 3553 NE2 GLN E 189 6.132 −67.519 −33.098 1.00 178.27 ATOM 3554 N LYS E 190 6.336 −70.806 −37.450 1.00 200.02 ATOM 3555 CA LYS E 190 5.905 −72.167 −37.252 1.00 198.97 ATOM 3556 C LYS E 190 5.136 −72.272 −35.958 1.00 200.06 ATOM 3557 O LYS E 190 5.558 −71.766 −34.914 1.00 197.60 ATOM 3558 CB LYS E 190 7.103 −73.121 −37.253 1.00 199.85 ATOM 3559 CG LYS E 190 6.695 −74.565 −37.055 1.00 201.00 ATOM 3560 CD LYS E 190 7.317 −75.479 −38.067 1.00 201.21 ATOM 3561 CE LYS E 190 6.892 −76.890 −37.824 1.00 196.41 ATOM 3562 NZ LYS E 190 5.436 −77.048 −38.088 1.00 200.37 ATOM 3563 N VAL E 191 3.992 −72.902 −36.042 1.00 196.89 ATOM 3564 CA VAL E 191 3.192 −73.131 −34.870 1.00 195.54 ATOM 3565 C VAL E 191 2.886 −74.600 −34.861 1.00 203.61 ATOM 3566 O VAL E 191 2.581 −75.213 −35.904 1.00 206.78 ATOM 3567 CB VAL E 191 1.956 −72.228 −34.778 1.00 199.71 ATOM 3568 CG1 VAL E 191 1.022 −72.680 −33.664 1.00 198.45 ATOM 3569 CG2 VAL E 191 2.372 −70.796 −34.539 1.00 199.28 ATOM 3570 N CYS E 192 3.079 −75.177 −33.679 1.00 197.95 ATOM 3571 CA CYS E 192 2.854 −76.575 −33.446 1.00 196.95 ATOM 3572 C CYS E 192 1.668 −76.657 −32.556 1.00 196.24 ATOM 3573 O CYS E 192 1.461 −75.725 −31.775 1.00 194.33 ATOM 3574 CB CYS E 192 4.079 −77.203 −32.797 1.00 195.85 ATOM 3575 SG CYS E 192 5.474 −77.452 −33.933 1.00 200.43 ATOM 3576 N PRO E 193 0.870 −77.738 −32.638 1.00 191.90 ATOM 3577 CA PRO E 193 −0.277 −77.834 −31.739 1.00 191.75 ATOM 3578 C PRO E 193 0.153 −77.624 −30.296 1.00 191.85 ATOM 3579 O PRO E 193 1.299 −77.876 −29.931 1.00 189.70 ATOM 3580 CB PRO E 193 −0.838 −79.242 −31.987 1.00 195.05 ATOM 3581 CG PRO E 193 0.146 −79.956 −32.838 1.00 199.45 ATOM 3582 CD PRO E 193 0.974 −78.917 −33.525 1.00 194.71 ATOM 3583 N THR E 194 −0.765 −77.097 −29.509 1.00 188.45 ATOM 3584 CA THR E 194 −0.674 −76.804 −28.083 1.00 186.94 ATOM 3585 C THR E 194 −0.080 −78.031 −27.305 1.00 187.89 ATOM 3586 O THR E 194 0.796 −77.867 −26.447 1.00 184.52 ATOM 3587 CB THR E 194 −2.116 −76.387 −27.652 1.00 200.85 ATOM 3588 OG1 THR E 194 −3.045 −77.429 −28.026 1.00 206.95 ATOM 3589 CG2 THR E 194 −2.599 −75.064 −28.329 1.00 196.58 ATOM 3590 N ILE E 195 −0.552 −79.256 −27.676 1.00 184.86 ATOM 3591 CA ILE E 195 −0.138 −80.561 −27.143 1.00 182.66 ATOM 3592 C ILE E 195 1.321 −80.910 −27.361 1.00 185.08 ATOM 3593 O ILE E 195 1.830 −81.696 −26.567 1.00 183.77 ATOM 3594 CB ILE E 195 −1.066 −81.706 −27.545 1.00 186.90 ATOM 3595 CG1 ILE E 195 −1.539 −81.581 −28.998 1.00 188.35 ATOM 3596 CG2 ILE E 195 −2.227 −81.740 −26.612 1.00 189.53 ATOM 3597 CD1 ILE E 195 −0.701 −82.293 −29.975 1.00 193.63 ATOM 3598 N CYS E 196 2.004 −80.330 −28.403 1.00 182.07 ATOM 3599 CA CYS E 196 3.454 −80.532 −28.689 1.00 180.96 ATOM 3600 C CYS E 196 4.298 −79.810 −27.700 1.00 183.24 ATOM 3601 O CYS E 196 5.511 −80.068 −27.620 1.00 181.86 ATOM 3602 CB CYS E 196 3.857 −80.105 −30.098 1.00 182.26 ATOM 3603 SG CYS E 196 3.214 −81.133 −31.427 1.00 189.29 ATOM 3604 N LYS E 197 3.689 −78.817 −27.036 1.00 180.01 ATOM 3605 CA LYS E 197 4.386 −77.988 −26.088 1.00 179.37 ATOM 3606 C LYS E 197 5.592 −77.370 −26.801 1.00 183.81 ATOM 3607 O LYS E 197 5.460 −76.846 −27.925 1.00 183.81 ATOM 3608 CB LYS E 197 4.782 −78.820 −24.848 1.00 181.51 ATOM 3609 CG LYS E 197 3.567 −79.278 −24.101 1.00 201.75 ATOM 3610 CD LYS E 197 3.869 −80.374 −23.128 1.00 216.14 ATOM 3611 CE LYS E 197 3.010 −80.251 −21.886 1.00 233.01 ATOM 3612 NZ LYS E 197 1.773 −79.440 −22.108 1.00 246.37 ATOM 3613 N SER E 198 6.764 −77.499 −26.178 1.00 179.29 ATOM 3614 CA SER E 198 7.971 −76.926 −26.706 1.00 177.90 ATOM 3615 C SER E 198 8.762 −77.908 −27.513 1.00 182.02 ATOM 3616 O SER E 198 9.793 −77.516 −28.020 1.00 181.95 ATOM 3617 CB SER E 198 8.814 −76.376 −25.563 1.00 179.03 ATOM 3618 OG SER E 198 9.163 −77.392 −24.636 1.00 184.16 ATOM 3619 N HIS E 199 8.292 −79.152 −27.684 1.00 178.64 ATOM 3620 CA HIS E 199 9.076 −80.167 −28.388 1.00 178.99 ATOM 3621 C HIS E 199 9.260 −79.986 −29.852 1.00 182.92 ATOM 3622 O HIS E 199 10.212 −80.548 −30.400 1.00 183.12 ATOM 3623 CB HIS E 199 8.567 −81.560 −28.072 1.00 181.30 ATOM 3624 CG HIS E 199 8.419 −81.773 −26.603 1.00 184.43 ATOM 3625 ND1 HIS E 199 7.245 −82.222 −26.060 1.00 187.26 ATOM 3626 CD2 HIS E 199 9.309 −81.545 −25.602 1.00 185.15 ATOM 3627 CE1 HIS E 199 7.454 −82.276 −24.755 1.00 186.09 ATOM 3628 NE2 HIS E 199 8.684 −81.878 −24.433 1.00 185.13 ATOM 3629 N GLY E 200 8.388 −79.198 −30.472 1.00 180.45 ATOM 3630 CA GLY E 200 8.418 −78.996 −31.913 1.00 183.08 ATOM 3631 C GLY E 200 7.634 −80.085 −32.616 1.00 193.28 ATOM 3632 O GLY E 200 7.159 −81.035 −31.977 1.00 193.78 ATOM 3633 N CYS E 201 7.501 −79.968 −33.940 1.00 193.98 ATOM 3634 CA CYS E 201 6.724 −80.919 −34.716 1.00 197.23 ATOM 3635 C CYS E 201 7.224 −80.927 −36.143 1.00 205.27 ATOM 3636 O CYS E 201 7.975 −80.026 −36.543 1.00 204.56 ATOM 3637 CB CYS E 201 5.245 −80.535 −34.657 1.00 198.65 ATOM 3638 SG CYS E 201 4.876 −78.864 −35.290 1.00 203.52 ATOM 3639 N THR E 202 6.760 −81.916 −36.927 1.00 205.46 ATOM 3640 CA THR E 202 7.034 −82.008 −38.366 1.00 208.27 ATOM 3641 C THR E 202 6.047 −81.082 −39.109 1.00 213.53 ATOM 3642 O THR E 202 5.137 −80.510 −38.498 1.00 210.98 ATOM 3643 CB THR E 202 6.894 −83.459 −38.871 1.00 215.67 ATOM 3644 OG1 THR E 202 5.535 −83.881 −38.722 1.00 214.92 ATOM 3645 CG2 THR E 202 7.824 −84.423 −38.143 1.00 211.75 ATOM 3646 N ALA E 203 6.198 −80.976 −40.438 1.00 213.89 ATOM 3647 CA ALA E 203 5.324 −80.153 −41.274 1.00 215.97 ATOM 3648 C ALA E 203 3.875 −80.586 −41.142 1.00 221.64 ATOM 3649 O ALA E 203 2.973 −79.751 −41.183 1.00 220.99 ATOM 3650 CB ALA E 203 5.761 −80.239 −42.729 1.00 220.08 ATOM 3651 N GLU E 204 3.662 −81.885 −40.921 1.00 220.30 ATOM 3652 CA GLU E 204 2.331 −82.468 −40.796 1.00 221.75 ATOM 3653 C GLU E 204 1.722 −82.304 −39.405 1.00 222.36 ATOM 3654 O GLU E 204 0.619 −82.798 −39.179 1.00 223.65 ATOM 3655 CB GLU E 204 2.328 −83.946 −41.222 1.00 225.45 ATOM 3656 CG GLU E 204 2.751 −84.177 −42.660 1.00 240.95 ATOM 3657 CD GLU E 204 4.246 −84.260 −42.918 1.00 264.56 ATOM 3658 OE1 GLU E 204 5.037 −84.278 −41.946 1.00 251.75 ATOM 3659 OE2 GLU E 204 4.625 −84.334 −44.109 1.00 264.86 ATOM 3660 N GLY E 205 2.429 −81.620 −38.499 1.00 213.75 ATOM 3661 CA GLY E 205 1.973 −81.362 −37.133 1.00 209.67 ATOM 3662 C GLY E 205 2.233 −82.449 −36.104 1.00 207.40 ATOM 3663 O GLY E 205 1.697 −82.372 −34.999 1.00 204.50 ATOM 3664 N LEU E 206 3.068 −83.454 −36.442 1.00 202.15 ATOM 3665 CA LEU E 206 3.381 −84.583 −35.560 1.00 199.62 ATOM 3666 C LEU E 206 4.479 −84.229 −34.593 1.00 199.11 ATOM 3667 O LEU E 206 5.573 −83.817 −34.996 1.00 198.85 ATOM 3668 CB LEU E 206 3.711 −85.850 −36.353 1.00 201.68 ATOM 3669 CG LEU E 206 2.693 −86.250 −37.414 1.00 209.58 ATOM 3670 CD1 LEU E 206 3.210 −87.386 −38.249 1.00 212.56 ATOM 3671 CD2 LEU E 206 1.356 −86.603 −36.796 1.00 212.60 ATOM 3672 N CYS E 207 4.167 −84.346 −33.305 1.00 192.00 ATOM 3673 CA CYS E 207 5.103 −83.949 −32.268 1.00 188.28 ATOM 3674 C CYS E 207 6.402 −84.684 −32.320 1.00 191.81 ATOM 3675 O CYS E 207 6.453 −85.891 −32.576 1.00 192.11 ATOM 3676 CB CYS E 207 4.489 −83.992 −30.869 1.00 186.78 ATOM 3677 SG CYS E 207 2.987 −82.984 −30.648 1.00 190.37 ATOM 3678 N CYS E 208 7.460 −83.925 −32.101 1.00 188.67 ATOM 3679 CA CYS E 208 8.808 −84.445 −31.942 1.00 190.08 ATOM 3680 C CYS E 208 8.847 −85.221 −30.624 1.00 192.39 ATOM 3681 O CYS E 208 7.927 −85.055 −29.814 1.00 192.43 ATOM 3682 CB CYS E 208 9.793 −83.287 −31.907 1.00 190.05 ATOM 3683 SG CYS E 208 9.992 −82.455 −33.498 1.00 196.29 ATOM 3684 N HIS E 209 9.913 −86.034 −30.385 1.00 185.95 ATOM 3685 CA HIS E 209 10.066 −86.717 −29.114 1.00 183.68 ATOM 3686 C HIS E 209 10.130 −85.669 −27.956 1.00 183.96 ATOM 3687 O HIS E 209 10.622 −84.548 −28.150 1.00 182.44 ATOM 3688 CB HIS E 209 11.332 −87.557 −29.129 1.00 185.10 ATOM 3689 CG HIS E 209 11.464 −88.460 −27.945 1.00 188.59 ATOM 3690 ND1 HIS E 209 12.135 −88.064 −26.806 1.00 188.81 ATOM 3691 CD2 HIS E 209 11.003 −89.718 −27.766 1.00 192.23 ATOM 3692 CE1 HIS E 209 12.056 −89.087 −25.973 1.00 189.35 ATOM 3693 NE2 HIS E 209 11.377 −90.102 −26.505 1.00 191.71 ATOM 3694 N SER E 210 9.634 −86.063 −26.761 1.00 178.93 ATOM 3695 CA SER E 210 9.591 −85.232 −25.560 1.00 176.10 ATOM 3696 C SER E 210 10.960 −84.770 −25.079 1.00 181.15 ATOM 3697 O SER E 210 11.024 −83.809 −24.312 1.00 180.28 ATOM 3698 CB SER E 210 8.820 −85.921 −24.448 1.00 176.55 ATOM 3699 OG SER E 210 9.326 −87.221 −24.243 1.00 178.71 ATOM 3700 N GLU E 211 12.052 −85.411 −25.536 1.00 179.29 ATOM 3701 CA GLU E 211 13.379 −84.931 −25.193 1.00 179.19 ATOM 3702 C GLU E 211 13.925 −83.916 −26.196 1.00 187.23 ATOM 3703 O GLU E 211 14.968 −83.319 −25.927 1.00 186.54 ATOM 3704 CB GLU E 211 14.357 −86.045 −24.895 1.00 181.65 ATOM 3705 CG GLU E 211 15.003 −85.753 −23.552 1.00 190.28 ATOM 3706 CD GLU E 211 14.145 −86.008 −22.322 1.00 208.96 ATOM 3707 OE1 GLU E 211 13.749 −87.175 −22.088 1.00 212.02 ATOM 3708 OE2 GLU E 211 13.804 −85.032 −21.619 1.00 194.96 ATOM 3709 N CYS E 212 13.203 −83.699 −27.340 1.00 187.44 ATOM 3710 CA CYS E 212 13.573 −82.700 −28.363 1.00 188.30 ATOM 3711 C CYS E 212 13.136 −81.349 −27.962 1.00 185.37 ATOM 3712 O CYS E 212 12.213 −81.223 −27.153 1.00 184.16 ATOM 3713 CB CYS E 212 13.043 −83.038 −29.750 1.00 192.77 ATOM 3714 SG CYS E 212 13.437 −84.712 −30.321 1.00 201.00 ATOM 3715 N LEU E 213 13.778 −80.321 −28.560 1.00 178.14 ATOM 3716 CA LEU E 213 13.427 −78.939 −28.256 1.00 174.85 ATOM 3717 C LEU E 213 12.730 −78.115 −29.322 1.00 181.05 ATOM 3718 O LEU E 213 11.573 −77.842 −29.089 1.00 182.31 ATOM 3719 CB LEU E 213 14.430 −78.161 −27.391 1.00 172.00 ATOM 3720 CG LEU E 213 14.077 −76.733 −26.969 1.00 172.79 ATOM 3721 CD1 LEU E 213 12.789 −76.657 −26.176 1.00 171.41 ATOM 3722 CD2 LEU E 213 15.108 −76.186 −26.101 1.00 173.41 ATOM 3723 N GLY E 214 13.297 −77.710 −30.430 1.00 177.83 ATOM 3724 CA GLY E 214 12.408 −76.899 −31.267 1.00 178.80 ATOM 3725 C GLY E 214 11.798 −77.541 −32.491 1.00 185.25 ATOM 3726 O GLY E 214 10.802 −77.066 −33.055 1.00 185.58 ATOM 3727 N ASN E 215 12.465 −78.577 −32.942 1.00 183.59 ATOM 3728 CA ASN E 215 12.222 −79.239 −34.205 1.00 186.15 ATOM 3729 C ASN E 215 12.980 −80.578 −34.219 1.00 189.51 ATOM 3730 O ASN E 215 13.840 −80.836 −33.372 1.00 185.67 ATOM 3731 CB ASN E 215 12.724 −78.282 −35.357 1.00 190.80 ATOM 3732 CG ASN E 215 12.320 −78.672 −36.751 1.00 212.57 ATOM 3733 OD1 ASN E 215 11.379 −79.463 −36.975 1.00 202.97 ATOM 3734 ND2 ASN E 215 13.006 −78.138 −37.743 1.00 205.29 ATOM 3735 N CYS E 216 12.635 −81.429 −35.171 1.00 190.90 ATOM 3736 CA CYS E 216 13.277 −82.723 −35.367 1.00 194.18 ATOM 3737 C CYS E 216 13.199 −83.083 −36.851 1.00 201.56 ATOM 3738 O CYS E 216 12.308 −82.578 −37.560 1.00 201.85 ATOM 3739 CB CYS E 216 12.591 −83.788 −34.511 1.00 194.92 ATOM 3740 SG CYS E 216 10.785 −83.870 −34.741 1.00 199.66 ATOM 3741 N SER E 217 14.113 −83.963 −37.311 1.00 200.11 ATOM 3742 CA SER E 217 14.098 −84.484 −38.673 1.00 203.78 ATOM 3743 C SER E 217 13.097 −85.653 −38.815 1.00 209.57 ATOM 3744 O SER E 217 12.623 −85.934 −39.919 1.00 212.30 ATOM 3745 CB SER E 217 15.498 −84.893 −39.109 1.00 210.14 ATOM 3746 OG SER E 217 16.017 −85.929 −38.296 1.00 220.07 ATOM 3747 N GLN E 218 12.783 −86.324 −37.697 1.00 204.74 ATOM 3748 CA GLN E 218 11.811 −87.407 −37.629 1.00 206.27 ATOM 3749 C GLN E 218 11.078 −87.331 −36.295 1.00 207.67 ATOM 3750 O GLN E 218 11.672 −86.948 −35.272 1.00 204.11 ATOM 3751 CB GLN E 218 12.484 −88.776 −37.736 1.00 210.43 ATOM 3752 CG GLN E 218 13.193 −89.050 −39.044 1.00 231.64 ATOM 3753 CD GLN E 218 13.910 −90.374 −39.024 1.00 263.13 ATOM 3754 OE1 GLN E 218 13.533 −91.321 −38.324 1.00 258.55 ATOM 3755 NE2 GLN E 218 14.910 −90.497 −39.868 1.00 265.01 ATOM 3756 N PRO E 219 9.784 −87.686 −36.279 1.00 205.72 ATOM 3757 CA PRO E 219 9.056 −87.672 −35.012 1.00 203.13 ATOM 3758 C PRO E 219 9.403 −88.866 −34.151 1.00 205.03 ATOM 3759 O PRO E 219 9.939 −89.878 −34.629 1.00 205.21 ATOM 3760 CB PRO E 219 7.594 −87.720 −35.443 1.00 206.63 ATOM 3761 CG PRO E 219 7.630 −88.510 −36.699 1.00 215.16 ATOM 3762 CD PRO E 219 8.922 −88.137 −37.391 1.00 211.09 ATOM 3763 N ASP E 220 9.101 −88.713 −32.870 1.00 200.59 ATOM 3764 CA ASP E 220 9.259 −89.747 −31.865 1.00 201.51 ATOM 3765 C ASP E 220 10.610 −90.486 −31.922 1.00 204.79 ATOM 3766 O ASP E 220 10.659 −91.718 −31.944 1.00 205.26 ATOM 3767 CB ASP E 220 8.052 −90.722 −31.922 1.00 206.33 ATOM 3768 CG ASP E 220 8.007 −91.812 −30.842 1.00 222.73 ATOM 3769 OD2 ASP E 220 7.492 −92.919 −31.132 1.00 229.67 ATOM 3770 OD1 ASP E 220 8.482 −91.554 −29.708 1.00 223.65 ATOM 3771 N ASP E 221 11.703 −89.725 −31.970 1.00 200.14 ATOM 3772 CA ASP E 221 13.038 −90.301 −31.941 1.00 201.22 ATOM 3773 C ASP E 221 13.999 −89.308 −31.313 1.00 203.38 ATOM 3774 O ASP E 221 14.260 −88.263 −31.914 1.00 202.75 ATOM 3775 CB ASP E 221 13.516 −90.721 −33.331 1.00 206.38 ATOM 3776 CG ASP E 221 14.791 −91.563 −33.342 1.00 221.59 ATOM 3777 OD2 ASP E 221 14.968 −92.352 −34.285 1.00 232.91 ATOM 3778 OD1 ASP E 221 15.638 −91.399 −32.426 1.00 220.89 ATOM 3779 N PRO E 222 14.565 −89.638 −30.126 1.00 199.08 ATOM 3780 CA PRO E 222 15.479 −88.701 −29.436 1.00 197.26 ATOM 3781 C PRO E 222 16.913 −88.570 −29.989 1.00 204.12 ATOM 3782 O PRO E 222 17.751 −87.858 −29.422 1.00 202.08 ATOM 3783 CB PRO E 222 15.445 −89.194 −27.991 1.00 197.96 ATOM 3784 CG PRO E 222 15.219 −90.643 −28.125 1.00 204.83 ATOM 3785 CD PRO E 222 14.336 −90.847 −29.316 1.00 201.58 ATOM 3786 N THR E 223 17.193 −89.252 −31.091 1.00 204.83 ATOM 3787 CA THR E 223 18.475 −89.166 −31.774 1.00 206.77 ATOM 3788 C THR E 223 18.265 −88.332 −33.048 1.00 210.61 ATOM 3789 O THR E 223 19.205 −88.161 −33.815 1.00 211.99 ATOM 3790 CB THR E 223 18.994 −90.583 −32.137 1.00 222.91 ATOM 3791 OG1 THR E 223 18.158 −91.150 −33.144 1.00 227.48 ATOM 3792 CG2 THR E 223 19.050 −91.532 −30.941 1.00 221.75 ATOM 3793 N LYS E 224 17.029 −87.851 −33.293 1.00 205.97 ATOM 3794 CA LYS E 224 16.676 −87.085 −34.494 1.00 206.43 ATOM 3795 C LYS E 224 16.219 −85.668 −34.189 1.00 208.74 ATOM 3796 O LYS E 224 15.622 −85.000 −35.045 1.00 209.72 ATOM 3797 CB LYS E 224 15.666 −87.849 −35.372 1.00 210.22 ATOM 3798 CG LYS E 224 16.362 −88.550 −36.545 1.00 214.13 ATOM 3799 CD LYS E 224 16.587 −90.009 −36.317 1.00 216.78 ATOM 3800 CE LYS E 224 17.714 −90.548 −37.152 1.00 213.82 ATOM 3801 NZ LYS E 224 18.903 −90.885 −36.325 1.00 213.01 ATOM 3802 N CYS E 225 16.543 −85.199 −32.978 1.00 202.54 ATOM 3803 CA CYS E 225 16.201 −83.844 −32.539 1.00 200.01 ATOM 3804 C CYS E 225 17.100 −82.815 −33.166 1.00 203.64 ATOM 3805 O CYS E 225 18.322 −83.020 −33.218 1.00 205.98 ATOM 3806 CB CYS E 225 16.296 −83.710 −31.023 1.00 198.04 ATOM 3807 SG CYS E 225 15.449 −84.987 −30.074 1.00 201.76 ATOM 3808 N VAL E 226 16.544 −81.632 −33.446 1.00 195.63 ATOM 3809 CA VAL E 226 17.382 −80.527 −33.863 1.00 193.79 ATOM 3810 C VAL E 226 18.045 −79.938 −32.580 1.00 190.14 ATOM 3811 O VAL E 226 19.196 −79.528 −32.634 1.00 189.89 ATOM 3812 CB VAL E 226 16.545 −79.490 −34.665 1.00 198.51 ATOM 3813 CG1 VAL E 226 17.259 −78.146 −34.790 1.00 198.10 ATOM 3814 CG2 VAL E 226 16.154 −80.036 −36.045 1.00 201.38 ATOM 3815 N ALA E 227 17.377 −80.038 −31.421 1.00 181.68 ATOM 3816 CA ALA E 227 17.812 −79.360 −30.216 1.00 178.85 ATOM 3817 C ALA E 227 18.266 −79.977 −28.861 1.00 181.77 ATOM 3818 O ALA E 227 19.373 −79.662 −28.428 1.00 182.09 ATOM 3819 CB ALA E 227 16.840 −78.241 −29.943 1.00 178.09 ATOM 3820 N CYS E 228 17.397 −80.666 −28.122 1.00 177.28 ATOM 3821 CA CYS E 228 17.491 −81.179 −26.728 1.00 176.49 ATOM 3822 C CYS E 228 16.879 −80.252 −25.740 1.00 177.34 ATOM 3823 O CYS E 228 17.385 −79.160 −25.485 1.00 175.88 ATOM 3824 CB CYS E 228 18.846 −81.671 −26.228 1.00 178.06 ATOM 3825 SG CYS E 228 19.586 −82.982 −27.222 1.00 185.37 ATOM 3826 N ARG E 229 15.803 −80.725 −25.130 1.00 172.07 ATOM 3827 CA ARG E 229 15.107 −80.045 −24.060 1.00 169.32 ATOM 3828 C ARG E 229 16.037 −80.036 −22.845 1.00 171.94 ATOM 3829 O ARG E 229 16.181 −78.991 −22.222 1.00 170.44 ATOM 3830 CB ARG E 229 13.811 −80.811 −23.752 1.00 169.44 ATOM 3831 CG ARG E 229 13.005 −80.291 −22.557 1.00 176.78 ATOM 3832 CD ARG E 229 11.739 −81.110 −22.320 1.00 183.66 ATOM 3833 NE ARG E 229 11.602 −81.565 −20.933 1.00 196.67 ATOM 3834 CZ ARG E 229 11.248 −82.799 −20.566 1.00 216.76 ATOM 3835 NH1 ARG E 229 10.938 −83.710 −21.482 1.00 205.45 ATOM 3836 NH2 ARG E 229 11.187 −83.125 −19.278 1.00 205.62 ATOM 3837 N ASN E 230 16.702 −81.187 −22.542 1.00 168.77 ATOM 3838 CA ASN E 230 17.552 −81.313 −21.377 1.00 167.70 ATOM 3839 C ASN E 230 19.041 −81.350 −21.694 1.00 171.91 ATOM 3840 O ASN E 230 19.685 −80.295 −21.806 1.00 171.26 ATOM 3841 CB ASN E 230 17.068 −82.468 −20.498 1.00 166.39 ATOM 3842 CG ASN E 230 15.679 −82.257 −19.929 1.00 189.24 ATOM 3843 OD1 ASN E 230 15.447 −81.349 −19.125 1.00 176.16 ATOM 3844 ND2 ASN E 230 14.735 −83.113 −20.300 1.00 187.51 ATOM 3845 N PHE E 231 19.593 −82.542 −21.823 1.00 169.51 ATOM 3846 CA PHE E 231 21.027 −82.694 −22.051 1.00 170.03 ATOM 3847 C PHE E 231 21.338 −83.536 −23.258 1.00 180.57 ATOM 3848 O PHE E 231 20.502 −84.315 −23.732 1.00 183.15 ATOM 3849 CB PHE E 231 21.739 −83.248 −20.801 1.00 170.77 ATOM 3850 CG PHE E 231 21.669 −82.314 −19.631 1.00 168.59 ATOM 3851 CD2 PHE E 231 20.826 −82.572 −18.573 1.00 168.66 ATOM 3852 CD1 PHE E 231 22.460 −81.176 −19.585 1.00 169.39 ATOM 3853 CE2 PHE E 231 20.730 −81.681 −17.518 1.00 170.35 ATOM 3854 CE1 PHE E 231 22.371 −80.290 −18.526 1.00 168.72 ATOM 3855 CZ PHE E 231 21.483 −80.531 −17.517 1.00 167.63 ATOM 3856 N TYR E 232 22.553 −83.379 −23.758 1.00 178.78 ATOM 3857 CA TYR E 232 23.002 −84.076 −24.943 1.00 181.33 ATOM 3858 C TYR E 232 24.126 −85.031 −24.598 1.00 188.12 ATOM 3859 O TYR E 232 25.118 −84.640 −23.981 1.00 187.86 ATOM 3860 CB TYR E 232 23.434 −83.073 −26.048 1.00 182.96 ATOM 3861 CG TYR E 232 24.169 −83.761 −27.168 1.00 188.24 ATOM 3862 CD1 TYR E 232 23.478 −84.463 −28.152 1.00 190.91 ATOM 3863 CD2 TYR E 232 25.558 −83.851 −27.159 1.00 192.07 ATOM 3864 CE1 TYR E 232 24.157 −85.193 −29.132 1.00 194.36 ATOM 3865 CE2 TYR E 232 26.247 −84.589 −28.122 1.00 196.58 ATOM 3866 CZ TYR E 232 25.544 −85.254 −29.113 1.00 202.92 ATOM 3867 OH TYR E 232 26.242 −85.959 −30.066 1.00 204.39 ATOM 3868 N LEU E 233 24.009 −86.270 −25.055 1.00 186.93 ATOM 3869 CA LEU E 233 25.053 −87.255 −24.837 1.00 189.08 ATOM 3870 C LEU E 233 25.076 −88.271 −25.937 1.00 196.05 ATOM 3871 O LEU E 233 24.048 −88.894 −26.217 1.00 196.57 ATOM 3872 CB LEU E 233 24.803 −87.976 −23.499 1.00 188.91 ATOM 3873 CG LEU E 233 25.840 −88.976 −23.044 1.00 197.11 ATOM 3874 CD1 LEU E 233 25.913 −88.996 −21.554 1.00 196.53 ATOM 3875 CD2 LEU E 233 25.472 −90.343 −23.432 1.00 203.06 ATOM 3876 N ASP E 234 26.267 −88.508 −26.497 1.00 194.45 ATOM 3877 CA ASP E 234 26.513 −89.566 −27.469 1.00 197.78 ATOM 3878 C ASP E 234 25.394 −89.705 −28.523 1.00 200.31 ATOM 3879 O ASP E 234 24.749 −90.755 −28.626 1.00 200.30 ATOM 3880 CB ASP E 234 26.760 −90.901 −26.718 1.00 202.51 ATOM 3881 CG ASP E 234 27.990 −90.947 −25.793 1.00 218.00 ATOM 3882 OD1 ASP E 234 28.975 −90.223 −26.068 1.00 220.21 ATOM 3883 OD2 ASP E 234 27.991 −91.763 −24.832 1.00 224.79 ATOM 3884 N GLY E 235 25.157 −88.608 −29.246 1.00 194.76 ATOM 3885 CA GLY E 235 24.162 −88.491 −30.311 1.00 193.46 ATOM 3886 C GLY E 235 22.719 −88.267 −29.895 1.00 191.83 ATOM 3887 O GLY E 235 21.894 −87.848 −30.714 1.00 191.15 ATOM 3888 N ARG E 236 22.429 −88.425 −28.614 1.00 184.64 ATOM 3889 CA ARG E 236 21.075 −88.474 −28.098 1.00 181.72 ATOM 3890 C ARG E 236 20.665 −87.397 −27.115 1.00 184.51 ATOM 3891 O ARG E 236 21.499 −86.889 −26.383 1.00 183.01 ATOM 3892 CB ARG E 236 20.975 −89.845 −27.432 1.00 178.95 ATOM 3893 CG ARG E 236 19.605 −90.315 −27.004 1.00 168.89 ATOM 3894 CD ARG E 236 19.717 −91.687 −26.407 1.00 159.23 ATOM 3895 NE ARG E 236 20.237 −91.578 −25.056 1.00 145.55 ATOM 3896 CZ ARG E 236 20.763 −92.577 −24.373 1.00 164.02 ATOM 3897 NH1 ARG E 236 20.892 −93.774 −24.929 1.00 174.66 ATOM 3898 NH2 ARG E 236 21.169 −92.392 −23.125 1.00 136.33 ATOM 3899 N CYS E 237 19.367 −87.073 −27.074 1.00 181.84 ATOM 3900 CA CYS E 237 18.811 −86.151 −26.090 1.00 180.10 ATOM 3901 C CYS E 237 18.350 −86.975 −24.907 1.00 178.68 ATOM 3902 O CYS E 237 17.511 −87.879 −25.061 1.00 178.98 ATOM 3903 CB CYS E 237 17.657 −85.332 −26.663 1.00 180.99 ATOM 3904 SG CYS E 237 18.127 −84.191 −27.982 1.00 186.15 ATOM 3905 N VAL E 238 18.922 −86.671 −23.733 1.00 170.90 ATOM 3906 CA VAL E 238 18.649 −87.339 −22.460 1.00 170.29 ATOM 3907 C VAL E 238 18.136 −86.410 −21.367 1.00 171.95 ATOM 3908 O VAL E 238 18.523 −85.242 −21.307 1.00 171.49 ATOM 3909 CB VAL E 238 19.844 −88.155 −21.938 1.00 176.29 ATOM 3910 CG1 VAL E 238 20.236 −89.229 −22.923 1.00 179.25 ATOM 3911 CG2 VAL E 238 21.035 −87.273 −21.600 1.00 175.35 ATOM 3912 N GLU E 239 17.298 −86.952 −20.469 1.00 166.95 ATOM 3913 CA GLU E 239 16.746 −86.196 −19.350 1.00 164.49 ATOM 3914 C GLU E 239 17.816 −85.742 −18.361 1.00 165.04 ATOM 3915 O GLU E 239 17.792 −84.607 −17.898 1.00 162.71 ATOM 3916 CB GLU E 239 15.612 −86.966 −18.658 1.00 166.86 ATOM 3917 CG GLU E 239 15.056 −86.211 −17.458 1.00 178.27 ATOM 3918 CD GLU E 239 13.861 −86.812 −16.750 1.00 195.68 ATOM 3919 OE1 GLU E 239 12.903 −87.223 −17.447 1.00 200.78 ATOM 3920 OE2 GLU E 239 13.912 −86.933 −15.502 1.00 176.05 ATOM 3921 N THR E 240 18.731 −86.615 −18.036 1.00 163.00 ATOM 3922 CA THR E 240 19.809 −86.268 −17.128 1.00 163.69 ATOM 3923 C THR E 240 21.061 −86.950 −17.584 1.00 171.24 ATOM 3924 O THR E 240 20.979 −87.966 −18.279 1.00 172.30 ATOM 3925 CB THR E 240 19.466 −86.661 −15.676 1.00 171.77 ATOM 3926 OG1 THR E 240 20.562 −86.291 −14.842 1.00 169.89 ATOM 3927 CG2 THR E 240 19.126 −88.161 −15.518 1.00 171.47 ATOM 3928 N CYS E 241 22.225 −86.427 −17.172 1.00 170.09 ATOM 3929 CA CYS E 241 23.498 −87.092 −17.445 1.00 173.33 ATOM 3930 C CYS E 241 23.584 −88.247 −16.483 1.00 178.41 ATOM 3931 O CYS E 241 23.487 −88.022 −15.274 1.00 179.17 ATOM 3932 CB CYS E 241 24.685 −86.160 −17.243 1.00 174.36 ATOM 3933 SG CYS E 241 24.768 −84.789 −18.415 1.00 176.76 ATOM 3934 N PRO E 242 23.758 −89.493 −16.930 1.00 173.89 ATOM 3935 CA PRO E 242 23.875 −90.543 −15.937 1.00 174.49 ATOM 3936 C PRO E 242 25.338 −90.609 −15.497 1.00 177.38 ATOM 3937 O PRO E 242 26.222 −90.161 −16.253 1.00 178.05 ATOM 3938 CB PRO E 242 23.473 −91.782 −16.727 1.00 178.23 ATOM 3939 CG PRO E 242 23.988 −91.519 −18.120 1.00 182.91 ATOM 3940 CD PRO E 242 23.916 −90.012 −18.311 1.00 175.89 ATOM 3941 N PRO E 243 25.619 −91.159 −14.300 1.00 171.55 ATOM 3942 CA PRO E 243 27.010 −91.418 −13.921 1.00 172.24 ATOM 3943 C PRO E 243 27.573 −92.501 −14.863 1.00 175.78 ATOM 3944 O PRO E 243 26.833 −93.370 −15.337 1.00 173.94 ATOM 3945 CB PRO E 243 26.880 −91.929 −12.504 1.00 175.93 ATOM 3946 CG PRO E 243 25.482 −91.534 −12.068 1.00 178.13 ATOM 3947 CD PRO E 243 24.693 −91.678 −13.282 1.00 172.74 ATOM 3948 N PRO E 244 28.840 −92.402 −15.262 1.00 175.61 ATOM 3949 CA PRO E 244 29.867 −91.504 −14.730 1.00 176.16 ATOM 3950 C PRO E 244 30.045 −90.152 −15.388 1.00 176.33 ATOM 3951 O PRO E 244 31.144 −89.613 −15.282 1.00 175.83 ATOM 3952 CB PRO E 244 31.134 −92.347 −14.889 1.00 183.05 ATOM 3953 CG PRO E 244 30.899 −93.085 −16.183 1.00 188.34 ATOM 3954 CD PRO E 244 29.422 −93.399 −16.186 1.00 181.08 ATOM 3955 N TYR E 245 29.019 −89.620 −16.087 1.00 170.74 ATOM 3956 CA TYR E 245 29.122 −88.316 −16.765 1.00 168.23 ATOM 3957 C TYR E 245 28.647 −87.138 −15.899 1.00 171.37 ATOM 3958 O TYR E 245 27.802 −87.325 −15.029 1.00 171.59 ATOM 3959 CB TYR E 245 28.392 −88.297 −18.115 1.00 167.68 ATOM 3960 CG TYR E 245 28.817 −89.405 −19.037 1.00 172.59 ATOM 3961 CD2 TYR E 245 28.012 −90.520 −19.228 1.00 174.89 ATOM 3962 CD1 TYR E 245 30.026 −89.349 −19.720 1.00 177.10 ATOM 3963 CE2 TYR E 245 28.418 −91.586 −20.036 1.00 179.69 ATOM 3964 CE1 TYR E 245 30.440 −90.402 −20.550 1.00 183.64 ATOM 3965 CZ TYR E 245 29.642 −91.534 −20.690 1.00 190.76 ATOM 3966 OH TYR E 245 30.051 −92.601 −21.479 1.00 191.98 ATOM 3967 N TYR E 246 29.170 −85.927 −16.153 1.00 165.73 ATOM 3968 CA TYR E 246 28.772 −84.709 −15.443 1.00 162.26 ATOM 3969 C TYR E 246 28.029 −83.726 −16.339 1.00 166.24 ATOM 3970 O TYR E 246 28.310 −83.613 −17.542 1.00 165.15 ATOM 3971 CB TYR E 246 29.980 −84.019 −14.833 1.00 162.58 ATOM 3972 CG TYR E 246 30.714 −84.906 −13.866 1.00 164.56 ATOM 3973 CD2 TYR E 246 31.876 −85.573 −14.245 1.00 167.65 ATOM 3974 CD1 TYR E 246 30.226 −85.116 −12.577 1.00 166.35 ATOM 3975 CE2 TYR E 246 32.541 −86.421 −13.363 1.00 171.41 ATOM 3976 CE1 TYR E 246 30.870 −85.976 −11.693 1.00 170.13 ATOM 3977 CZ TYR E 246 32.027 −86.628 −12.092 1.00 177.60 ATOM 3978 OH TYR E 246 32.684 −87.446 −11.217 1.00 179.34 ATOM 3979 N HIS E 247 27.085 −83.002 −15.728 1.00 163.05 ATOM 3980 CA HIS E 247 26.303 −81.987 −16.423 1.00 161.74 ATOM 3981 C HIS E 247 27.214 −80.776 −16.692 1.00 170.39 ATOM 3982 O HIS E 247 27.809 −80.230 −15.763 1.00 171.17 ATOM 3983 CB HIS E 247 25.101 −81.561 −15.579 1.00 160.54 ATOM 3984 CG HIS E 247 24.178 −82.667 −15.188 1.00 163.97 ATOM 3985 ND1 HIS E 247 23.055 −82.948 −15.924 1.00 164.60 ATOM 3986 CD2 HIS E 247 24.184 −83.454 −14.087 1.00 166.55 ATOM 3987 CE1 HIS E 247 22.413 −83.895 −15.261 1.00 164.36 ATOM 3988 NE2 HIS E 247 23.069 −84.251 −14.166 1.00 166.21 ATOM 3989 N PHE E 248 27.341 −80.374 −17.963 1.00 168.62 ATOM 3990 CA PHE E 248 28.215 −79.291 −18.361 1.00 169.08 ATOM 3991 C PHE E 248 27.499 −78.194 −19.133 1.00 175.91 ATOM 3992 O PHE E 248 26.724 −78.488 −20.063 1.00 176.30 ATOM 3993 CB PHE E 248 29.387 −79.862 −19.160 1.00 172.45 ATOM 3994 CG PHE E 248 30.457 −78.856 −19.464 1.00 174.50 ATOM 3995 CD1 PHE E 248 31.212 −78.298 −18.451 1.00 177.91 ATOM 3996 CD2 PHE E 248 30.705 −78.456 −20.765 1.00 176.89 ATOM 3997 CE1 PHE E 248 32.200 −77.371 −18.735 1.00 179.13 ATOM 3998 CE2 PHE E 248 31.689 −77.513 −21.045 1.00 180.41 ATOM 3999 CZ PHE E 248 32.427 −76.981 −20.029 1.00 178.75 ATOM 4000 N GLN E 249 27.751 −76.920 −18.724 1.00 173.25 ATOM 4001 CA GLN E 249 27.217 −75.708 −19.365 1.00 172.30 ATOM 4002 C GLN E 249 25.660 −75.772 −19.522 1.00 174.09 ATOM 4003 O GLN E 249 25.060 −75.164 −20.407 1.00 171.77 ATOM 4004 CB GLN E 249 27.971 −75.540 −20.705 1.00 175.01 ATOM 4005 CG GLN E 249 27.918 −74.230 −21.454 1.00 212.46 ATOM 4006 CD GLN E 249 28.384 −72.999 −20.728 1.00 242.40 ATOM 4007 OE1 GLN E 249 29.587 −72.741 −20.584 1.00 240.03 ATOM 4008 NE2 GLN E 249 27.418 −72.132 −20.422 1.00 232.89 ATOM 4009 N ASP E 250 25.030 −76.530 −18.635 1.00 171.84 ATOM 4010 CA ASP E 250 23.605 −76.765 −18.636 1.00 171.66 ATOM 4011 C ASP E 250 22.980 −77.295 −19.965 1.00 174.25 ATOM 4012 O ASP E 250 21.773 −77.114 −20.211 1.00 174.56 ATOM 4013 CB ASP E 250 22.834 −75.618 −17.976 1.00 173.92 ATOM 4014 CG ASP E 250 21.608 −76.123 −17.221 1.00 200.91 ATOM 4015 OD1 ASP E 250 21.786 −76.860 −16.201 1.00 202.99 ATOM 4016 OD2 ASP E 250 20.469 −75.833 −17.672 1.00 215.48 ATOM 4017 N TRP E 251 23.781 −78.033 −20.776 1.00 168.06 ATOM 4018 CA TRP E 251 23.271 −78.643 −22.009 1.00 166.25 ATOM 4019 C TRP E 251 23.944 −79.943 −22.441 1.00 173.07 ATOM 4020 O TRP E 251 23.356 −80.646 −23.263 1.00 175.39 ATOM 4021 CB TRP E 251 23.284 −77.644 −23.156 1.00 163.41 ATOM 4022 CG TRP E 251 24.616 −77.534 −23.776 1.00 165.28 ATOM 4023 CD1 TRP E 251 25.696 −76.885 −23.272 1.00 168.50 ATOM 4024 CD2 TRP E 251 25.063 −78.217 −24.948 1.00 166.95 ATOM 4025 NE1 TRP E 251 26.782 −77.077 −24.087 1.00 170.39 ATOM 4026 CE2 TRP E 251 26.418 −77.884 −25.134 1.00 172.74 ATOM 4027 CE3 TRP E 251 24.443 −79.062 −25.881 1.00 169.04 ATOM 4028 CZ2 TRP E 251 27.165 −78.362 −26.219 1.00 174.17 ATOM 4029 CZ3 TRP E 251 25.184 −79.533 −26.957 1.00 172.54 ATOM 4030 CH2 TRP E 251 26.529 −79.189 −27.113 1.00 174.62 ATOM 4031 N ARG E 252 25.186 −80.237 −21.980 1.00 168.79 ATOM 4032 CA ARG E 252 25.840 −81.492 −22.374 1.00 170.03 ATOM 4033 C ARG E 252 26.469 −82.315 −21.262 1.00 178.09 ATOM 4034 O ARG E 252 26.754 −81.791 −20.188 1.00 178.84 ATOM 4035 CB ARG E 252 26.796 −81.308 −23.544 1.00 167.70 ATOM 4036 CG ARG E 252 27.994 −80.487 −23.234 1.00 171.56 ATOM 4037 CD ARG E 252 29.021 −80.721 −24.302 1.00 183.53 ATOM 4038 NE ARG E 252 30.069 −79.699 −24.295 1.00 187.68 ATOM 4039 CZ ARG E 252 31.184 −79.756 −25.024 1.00 199.10 ATOM 4040 NH1 ARG E 252 31.386 −80.764 −25.865 1.00 186.77 ATOM 4041 NH2 ARG E 252 32.100 −78.799 −24.925 1.00 181.29 ATOM 4042 N CYS E 253 26.669 −83.626 −21.526 1.00 176.45 ATOM 4043 CA CYS E 253 27.288 −84.589 −20.595 1.00 177.27 ATOM 4044 C CYS E 253 28.687 −84.805 −20.954 1.00 183.35 ATOM 4045 O CYS E 253 28.994 −85.060 −22.117 1.00 184.02 ATOM 4046 CB CYS E 253 26.548 −85.910 −20.583 1.00 178.03 ATOM 4047 SG CYS E 253 24.807 −85.752 −20.194 1.00 178.88 ATOM 4048 N VAL E 254 29.554 −84.701 −19.964 1.00 181.36 ATOM 4049 CA VAL E 254 30.980 −84.870 −20.183 1.00 184.69 ATOM 4050 C VAL E 254 31.527 −85.816 −19.096 1.00 190.53 ATOM 4051 O VAL E 254 30.858 −86.040 −18.088 1.00 189.11 ATOM 4052 CB VAL E 254 31.720 −83.495 −20.233 1.00 188.69 ATOM 4053 CG1 VAL E 254 31.212 −82.589 −21.372 1.00 186.90 ATOM 4054 CG2 VAL E 254 31.643 −82.770 −18.887 1.00 187.36 ATOM 4055 N ASN E 255 32.723 −86.388 −19.311 1.00 189.58 ATOM 4056 CA ASN E 255 33.352 −87.278 −18.324 1.00 191.47 ATOM 4057 C ASN E 255 34.287 −86.480 −17.415 1.00 195.05 ATOM 4058 O ASN E 255 34.640 −85.325 −17.713 1.00 194.41 ATOM 4059 CB ASN E 255 34.103 −88.461 −18.995 1.00 195.05 ATOM 4060 CG ASN E 255 35.103 −87.988 −20.011 1.00 225.86 ATOM 4061 OD1 ASN E 255 35.831 −87.015 −19.779 1.00 226.15 ATOM 4062 ND2 ASN E 255 35.139 −88.582 −21.197 1.00 221.41 ATOM 4063 N PHE E 256 34.721 −87.107 −16.331 1.00 192.04 ATOM 4064 CA PHE E 256 35.630 −86.449 −15.410 1.00 192.52 ATOM 4065 C PHE E 256 36.881 −85.874 −16.101 1.00 197.04 ATOM 4066 O PHE E 256 37.316 −84.764 −15.799 1.00 194.58 ATOM 4067 CB PHE E 256 36.040 −87.424 −14.304 1.00 197.52 ATOM 4068 CG PHE E 256 37.098 −86.838 −13.411 1.00 200.33 ATOM 4069 CD1 PHE E 256 36.777 −85.858 −12.480 1.00 200.43 ATOM 4070 CD2 PHE E 256 38.428 −87.189 −13.568 1.00 206.43 ATOM 4071 CE1 PHE E 256 37.759 −85.272 −11.700 1.00 203.02 ATOM 4072 CE2 PHE E 256 39.405 −86.614 −12.776 1.00 211.12 ATOM 4073 CZ PHE E 256 39.068 −85.650 −11.859 1.00 206.77 ATOM 4074 N SER E 257 37.456 −86.656 −17.005 1.00 196.92 ATOM 4075 CA SER E 257 38.682 −86.334 −17.705 1.00 199.31 ATOM 4076 C SER E 257 38.568 −85.023 −18.490 1.00 200.87 ATOM 4077 O SER E 257 39.512 −84.241 −18.510 1.00 202.11 ATOM 4078 CB SER E 257 39.086 −87.513 −18.586 1.00 205.82 ATOM 4079 OG SER E 257 39.990 −87.157 −19.616 1.00 215.57 ATOM 4080 N PHE E 258 37.417 −84.781 −19.107 1.00 194.67 ATOM 4081 CA PHE E 258 37.145 −83.573 −19.863 1.00 193.56 ATOM 4082 C PHE E 258 37.149 −82.383 −18.925 1.00 196.85 ATOM 4083 O PHE E 258 37.763 −81.360 −19.242 1.00 197.66 ATOM 4084 CB PHE E 258 35.769 −83.687 −20.533 1.00 193.47 ATOM 4085 CG PHE E 258 35.248 −82.433 −21.221 1.00 193.05 ATOM 4086 CD1 PHE E 258 35.357 −82.279 −22.598 1.00 198.11 ATOM 4087 CD2 PHE E 258 34.607 −81.430 −20.493 1.00 192.08 ATOM 4088 CE1 PHE E 258 34.872 −81.125 −23.230 1.00 197.04 ATOM 4089 CE2 PHE E 258 34.107 −80.286 −21.126 1.00 192.93 ATOM 4090 CZ PHE E 258 34.245 −80.137 −22.487 1.00 192.43 ATOM 4091 N CYS E 259 36.441 −82.507 −17.780 1.00 191.14 ATOM 4092 CA CYS E 259 36.347 −81.442 −16.785 1.00 189.04 ATOM 4093 C CYS E 259 37.716 −81.114 −16.228 1.00 195.62 ATOM 4094 O CYS E 259 38.018 −79.953 −15.933 1.00 193.72 ATOM 4095 CB CYS E 259 35.387 −81.839 −15.674 1.00 188.02 ATOM 4096 SG CYS E 259 34.884 −80.461 −14.613 1.00 189.48 ATOM 4097 N GLN E 260 38.538 −82.159 −16.079 1.00 196.22 ATOM 4098 CA GLN E 260 39.896 −82.059 −15.569 1.00 198.96 ATOM 4099 C GLN E 260 40.800 −81.343 −16.545 1.00 203.73 ATOM 4100 O GLN E 260 41.579 −80.476 −16.141 1.00 203.71 ATOM 4101 CB GLN E 260 40.425 −83.448 −15.247 1.00 203.52 ATOM 4102 CG GLN E 260 41.820 −83.432 −14.727 1.00 210.19 ATOM 4103 CD GLN E 260 42.046 −84.671 −13.967 1.00 235.24 ATOM 4104 OE1 GLN E 260 42.017 −84.640 −12.741 1.00 232.48 ATOM 4105 NE2 GLN E 260 42.127 −85.808 −14.653 1.00 230.43 ATOM 4106 N ASP E 261 40.693 −81.700 −17.824 1.00 201.21 ATOM 4107 CA ASP E 261 41.476 −81.068 −18.874 1.00 202.91 ATOM 4108 C ASP E 261 41.196 −79.563 −18.954 1.00 202.01 ATOM 4109 O ASP E 261 42.128 −78.776 −19.123 1.00 203.66 ATOM 4110 CB ASP E 261 41.274 −81.795 −20.219 1.00 206.74 ATOM 4111 CG ASP E 261 41.890 −83.205 −20.304 1.00 228.81 ATOM 4112 OD1 ASP E 261 42.574 −83.631 −19.331 1.00 232.23 ATOM 4113 OD2 ASP E 261 41.684 −83.885 −21.338 1.00 239.48 ATOM 4114 N LEU E 262 39.935 −79.166 −18.769 1.00 193.04 ATOM 4115 CA LEU E 262 39.545 −77.759 −18.762 1.00 190.09 ATOM 4116 C LEU E 262 40.206 −77.017 −17.621 1.00 196.98 ATOM 4117 O LEU E 262 40.779 −75.938 −17.810 1.00 196.58 ATOM 4118 CB LEU E 262 38.039 −77.651 −18.585 1.00 185.89 ATOM 4119 CG LEU E 262 37.254 −77.483 −19.842 1.00 188.37 ATOM 4120 CD1 LEU E 262 37.318 −78.696 −20.776 1.00 190.26 ATOM 4121 CD2 LEU E 262 35.888 −77.000 −19.522 1.00 187.72 ATOM 4122 N HIS E 263 40.101 −77.603 −16.430 1.00 196.60 ATOM 4123 CA HIS E 263 40.650 −77.059 −15.201 1.00 198.83 ATOM 4124 C HIS E 263 42.129 −76.750 −15.316 1.00 210.08 ATOM 4125 O HIS E 263 42.562 −75.667 −14.907 1.00 211.45 ATOM 4126 CB HIS E 263 40.425 −78.037 −14.046 1.00 200.25 ATOM 4127 CG HIS E 263 41.020 −77.545 −12.771 1.00 205.01 ATOM 4128 ND1 EIS E 263 42.340 −77.810 −12.448 1.00 210.62 ATOM 4129 CD2 HIS E 263 40.482 −76.759 −11.813 1.00 204.98 ATOM 4130 CE1 HIS E 263 42.550 −77.204 −11.293 1.00 210.66 ATOM 4131 NE2 HIS E 263 41.464 −76.548 −10.880 1.00 207.70 ATOM 4132 N HIS E 264 42.899 −77.700 −15.874 1.00 210.08 ATOM 4133 CA HIS E 264 44.334 −77.564 −16.006 1.00 213.83 ATOM 4134 C HIS E 264 44.745 −76.516 −17.015 1.00 215.60 ATOM 4135 O HIS E 264 44.679 −76.693 −18.232 1.00 214.86 ATOM 4136 CB HIS E 264 45.026 −78.908 −15.998 1.00 219.06 ATOM 4137 CG HIS E 264 44.974 −79.534 −14.624 1.00 224.14 ATOM 4138 ND1 HIS E 264 44.109 −80.583 −14.325 1.00 225.26 ATOM 4139 CD2 HIS E 264 45.647 −79.199 −13.494 1.00 228.36 ATOM 4140 CE1 HIS E 264 44.321 −80.877 −13.047 1.00 226.38 ATOM 4141 NE2 HIS E 264 45.233 −80.070 −12.503 1.00 228.58 ATOM 4142 N LYS E 265 44.952 −75.325 −16.420 1.00 210.25 ATOM 4143 CA LYS E 265 45.170 −74.012 −16.996 1.00 212.48 ATOM 4144 C LYS E 265 44.014 −73.568 −17.860 1.00 204.27 ATOM 4145 O LYS E 265 42.966 −73.290 −17.286 1.00 158.06 ATOM 4146 CB LYS E 265 46.562 −73.780 −17.597 1.00 218.46 ATOM 4147 CG LYS E 265 47.391 −72.837 −16.716 1.00 216.10 ATOM 4148 CD LYS E 265 48.501 −72.077 −17.458 1.00 214.34 ATOM 4149 CE LYS E 265 48.035 −70.937 −18.355 1.00 208.08 ATOM 4150 NZ LYS E 265 47.450 −69.785 −17.608 1.00 204.39 ATOM 4151 N GLN E 276 38.818 −72.227 −13.908 1.00 191.28 ATOM 4152 CA GLN E 276 39.360 −73.495 −13.359 1.00 193.77 ATOM 4153 C GLN E 276 38.189 −74.323 −12.838 1.00 193.67 ATOM 4154 O GLN E 276 37.746 −74.132 −11.701 1.00 193.21 ATOM 4155 CB GLN E 276 40.375 −73.253 −12.211 1.00 198.53 ATOM 4156 CG GLN E 276 41.429 −72.154 −12.456 1.00 218.34 ATOM 4157 CD GLN E 276 41.875 −71.447 −11.185 1.00 233.70 ATOM 4158 OE1 GLN E 276 41.585 −70.260 −10.974 1.00 225.94 ATOM 4159 NE2 GLN E 276 42.624 −72.138 −10.330 1.00 225.95 ATOM 4160 N TYR E 277 37.671 −75.217 −13.698 1.00 186.44 ATOM 4161 CA TYR E 277 36.472 −76.022 −13.470 1.00 182.61 ATOM 4162 C TYR E 277 36.538 −76.980 −12.316 1.00 184.61 ATOM 4163 O TYR E 277 37.590 −77.543 −12.025 1.00 187.17 ATOM 4164 CB TYR E 277 36.032 −76.708 −14.756 1.00 182.96 ATOM 4165 CG TYR E 277 35.346 −75.747 −15.691 1.00 183.67 ATOM 4166 CD2 TYR E 277 33.962 −75.703 −15.780 1.00 183.09 ATOM 4167 CD1 TYR E 277 36.078 −74.856 −16.470 1.00 186.37 ATOM 4168 CE2 TYR E 277 33.316 −74.784 −16.612 1.00 182.67 ATOM 4169 CE1 TYR E 277 35.446 −73.936 −17.312 1.00 186.04 ATOM 4170 CZ TYR E 277 34.061 −73.906 −17.386 1.00 190.12 ATOM 4171 OH TYR E 277 33.417 −73.015 −18.224 1.00 186.10 ATOM 4172 N VAL E 278 35.413 −77.137 −11.629 1.00 176.19 ATOM 4173 CA VAL E 278 35.323 −77.984 −10.450 1.00 175.95 ATOM 4174 C VAL E 278 34.146 −78.932 −10.576 1.00 178.94 ATOM 4175 O VAL E 278 33.281 −78.736 −11.417 1.00 175.49 ATOM 4176 CB VAL E 278 35.218 −77.125 −9.168 1.00 178.67 ATOM 4177 CG1 VAL E 278 36.378 −76.158 −9.068 1.00 179.61 ATOM 4178 CG2 VAL E 278 33.918 −76.351 −9.126 1.00 175.44 ATOM 4179 N ILE E 279 34.109 −79.950 −9.741 1.00 178.71 ATOM 4180 CA ILE E 279 32.983 −80.854 −9.704 1.00 177.96 ATOM 4181 C ILE E 279 32.185 −80.521 −8.481 1.00 180.61 ATOM 4182 O ILE E 279 32.747 −80.374 −7.387 1.00 182.45 ATOM 4183 CB ILE E 279 33.424 −82.324 −9.738 1.00 184.55 ATOM 4184 CG1 ILE E 279 33.929 −82.646 −11.169 1.00 185.33 ATOM 4185 CG2 ILE E 279 32.228 −83.245 −9.409 1.00 185.19 ATOM 4186 CD1 ILE E 279 35.330 −82.731 −11.374 1.00 195.08 ATOM 4187 N HIS E 280 30.875 −80.395 −8.667 1.00 174.27 ATOM 4188 CA HIS E 280 29.936 −80.169 −7.585 1.00 174.67 ATOM 4189 C HIS E 280 28.530 −80.682 −7.960 1.00 178.26 ATOM 4190 O HIS E 280 28.011 −80.308 −9.018 1.00 175.61 ATOM 4191 CB HIS E 280 29.897 −78.697 −7.165 1.00 174.85 ATOM 4192 CG HIS E 280 28.883 −78.417 −6.086 1.00 178.88 ATOM 4193 ND1 HIS E 280 29.041 −78.914 −4.799 1.00 183.74 ATOM 4194 CD2 HIS E 280 27.723 −77.706 −6.139 1.00 178.62 ATOM 4195 CE1 HIS E 280 27.997 −78.475 −4.111 1.00 182.69 ATOM 4196 NE2 HIS E 280 27.175 −77.743 −4.873 1.00 179.98 ATOM 4197 N ASN E 281 27.909 −81.538 −7.091 1.00 176.15 ATOM 4198 CA ASN E 281 26.556 −82.079 −7.300 1.00 174.31 ATOM 4199 C ASN E 281 26.382 −82.688 −8.722 1.00 178.01 ATOM 4200 O ASN E 281 25.375 −82.431 −9.356 1.00 176.37 ATOM 4201 CB ASN E 281 25.533 −80.934 −7.067 1.00 170.92 ATOM 4202 CG ASN E 281 24.185 −81.288 −6.491 1.00 201.33 ATOM 4203 OD1 ASN E 281 23.125 −80.951 −7.060 1.00 189.94 ATOM 4204 ND2 ASN E 281 24.194 −81.867 −5.293 1.00 198.64 ATOM 4205 N ASN E 282 27.368 −83.445 −9.236 1.00 175.95 ATOM 4206 CA ASN E 282 27.313 −84.044 −10.583 1.00 174.61 ATOM 4207 C ASN E 282 27.289 −83.057 −11.779 1.00 172.46 ATOM 4208 O ASN E 282 26.823 −83.359 −12.888 1.00 169.71 ATOM 4209 CB ASN E 282 26.276 −85.140 −10.652 1.00 177.32 ATOM 4210 CG ASN E 282 26.653 −86.293 −9.757 1.00 199.67 ATOM 4211 OD1 ASN E 282 26.041 −86.507 −8.709 1.00 198.11 ATOM 4212 ND2 ASN E 282 27.675 −87.066 −10.152 1.00 186.89 ATOM 4213 N LYS E 283 27.864 −81.889 −11.526 1.00 166.53 ATOM 4214 CA LYS E 283 28.019 −80.843 −12.498 1.00 163.92 ATOM 4215 C LYS E 283 29.478 −80.479 −12.556 1.00 172.36 ATOM 4216 O LYS E 283 30.195 −80.562 −11.551 1.00 173.83 ATOM 4217 CB LYS E 283 27.208 −79.610 −12.100 1.00 163.61 ATOM 4218 CG LYS E 283 25.715 −79.854 −11.864 1.00 178.24 ATOM 4219 CD LYS E 283 25.133 −79.062 −10.645 1.00 180.11 ATOM 4220 CE LYS E 283 24.870 −77.611 −10.914 1.00 170.16 ATOM 4221 NZ LYS E 283 24.505 −76.911 −9.658 1.00 170.88 ATOM 4222 N CYS E 284 29.936 −80.122 −13.750 1.00 171.63 ATOM 4223 CA CYS E 284 31.280 −79.604 −13.969 1.00 174.37 ATOM 4224 C CYS E 284 31.036 −78.083 −14.085 1.00 172.81 ATOM 4225 O CYS E 284 30.343 −77.592 −14.975 1.00 170.16 ATOM 4226 CB CYS E 284 31.900 −80.212 −15.219 1.00 177.52 ATOM 4227 SG CYS E 284 33.468 −79.478 −15.699 1.00 184.66 ATOM 4228 N ILE E 285 31.514 −77.360 −13.110 1.00 167.81 ATOM 4229 CA ILE E 285 31.151 −75.983 −12.891 1.00 165.88 ATOM 4230 C ILE E 285 32.343 −75.039 −12.869 1.00 173.87 ATOM 4231 O ILE E 285 33.439 −75.431 −12.442 1.00 175.84 ATOM 4232 CB ILE E 285 30.439 −76.100 −11.509 1.00 168.65 ATOM 4233 CG1 ILE E 285 29.599 −74.938 −11.039 1.00 167.76 ATOM 4234 CG2 ILE E 285 31.313 −76.658 −10.386 1.00 171.28 ATOM 4235 CD1 ILE E 285 29.100 −75.205 −9.547 1.00 169.44 ATOM 4236 N PRO E 286 32.141 −73.775 −13.303 1.00 169.87 ATOM 4237 CA PRO E 286 33.255 −72.821 −13.306 1.00 171.04 ATOM 4238 C PRO E 286 33.909 −72.619 −11.948 1.00 177.18 ATOM 4239 O PRO E 286 35.132 −72.598 −11.869 1.00 178.90 ATOM 4240 CB PRO E 286 32.606 −71.533 −13.800 1.00 171.25 ATOM 4241 CG PRO E 286 31.413 −71.988 −14.565 1.00 173.71 ATOM 4242 CD PRO E 286 30.904 −73.162 −13.832 1.00 168.94 ATOM 4243 N GLU E 287 33.086 −72.536 −10.886 1.00 175.35 ATOM 4244 CA GLU E 287 33.483 −72.227 −9.524 1.00 179.30 ATOM 4245 C GLU E 287 32.684 −72.941 −8.477 1.00 185.14 ATOM 4246 O GLU E 287 31.479 −73.114 −8.642 1.00 183.17 ATOM 4247 CB GLU E 287 33.149 −70.743 −9.329 1.00 181.09 ATOM 4248 CG GLU E 287 33.802 −70.009 −8.169 1.00 204.13 ATOM 4249 CD GLU E 287 33.543 −68.513 −8.237 1.00 236.59 ATOM 4250 OE1 GLU E 287 32.369 −68.113 −8.051 1.00 235.43 ATOM 4251 OE2 GLU E 287 34.501 −67.743 −8.497 1.00 228.91 ATOM 4252 N CYS E 288 33.319 −73.190 −7.323 1.00 185.23 ATOM 4253 CA CYS E 288 32.673 −73.748 −6.145 1.00 186.51 ATOM 4254 C CYS E 288 31.626 −72.785 −5.637 1.00 192.78 ATOM 4255 O CYS E 288 31.913 −71.589 −5.540 1.00 194.38 ATOM 4256 CB CYS E 288 33.701 −73.995 −5.052 1.00 189.71 ATOM 4257 SG CYS E 288 34.482 −75.631 −5.092 1.00 195.13 ATOM 4258 N PRO E 289 30.459 −73.289 −5.208 1.00 188.79 ATOM 4259 CA PRO E 289 29.454 −72.410 −4.617 1.00 188.26 ATOM 4260 C PRO E 289 29.840 −72.031 −3.189 1.00 195.65 ATOM 4261 O PRO E 289 30.821 −72.543 −2.630 1.00 196.23 ATOM 4262 CB PRO E 289 28.189 −73.258 −4.645 1.00 188.54 ATOM 4263 CG PRO E 289 28.670 −74.618 −4.528 1.00 194.14 ATOM 4264 CD PRO E 289 29.982 −74.678 −5.255 1.00 190.12 ATOM 4265 N SER E 290 29.055 −71.117 −2.612 1.00 194.08 ATOM 4266 CA SER E 290 29.224 −70.601 −1.266 1.00 197.22 ATOM 4267 C SER E 290 29.125 −71.737 −0.249 1.00 202.02 ATOM 4268 O SER E 290 28.219 −72.573 −0.338 1.00 199.64 ATOM 4269 CB SER E 290 28.168 −69.533 −0.992 1.00 201.26 ATOM 4270 OG SER E 290 27.960 −68.703 −2.129 1.00 206.63 ATOM 4271 N GLY E 291 30.084 −71.753 0.673 1.00 201.64 ATOM 4272 CA GLY E 291 30.202 −72.738 1.744 1.00 204.28 ATOM 4273 C GLY E 291 31.189 −73.842 1.441 1.00 208.32 ATOM 4274 O GLY E 291 31.483 −74.683 2.304 1.00 210.27 ATOM 4275 N TYR E 292 31.727 −73.815 0.212 1.00 202.91 ATOM 4276 CA TYR E 292 32.633 −74.827 −0.302 1.00 203.52 ATOM 4277 C TYR E 292 33.926 −74.254 −0.829 1.00 210.70 ATOM 4278 O TYR E 292 33.974 −73.088 −1.227 1.00 210.31 ATOM 4279 CB TYR E 292 31.954 −75.561 −1.462 1.00 200.66 ATOM 4280 CG TYR E 292 30.752 −76.382 −1.071 1.00 200.53 ATOM 4281 CD1 TYR E 292 30.894 −77.700 −0.668 1.00 204.04 ATOM 4282 CD2 TYR E 292 29.463 −75.891 −1.244 1.00 198.37 ATOM 4283 CE1 TYR E 292 29.799 −78.468 −0.321 1.00 204.00 ATOM 4284 CE2 TYR E 292 28.355 −76.653 −0.902 1.00 198.68 ATOM 4285 CZ TYR E 292 28.533 −77.941 −0.434 1.00 207.73 ATOM 4286 OH TYR E 292 27.471 −78.733 −0.102 1.00 211.91 ATOM 4287 N THR E 293 34.979 −75.090 −0.826 1.00 209.62 ATOM 4288 CA THR E 293 36.283 −74.817 −1.399 1.00 210.52 ATOM 4289 C THR E 293 36.746 −76.039 −2.123 1.00 215.50 ATOM 4290 O THR E 293 36.247 −77.141 −1.876 1.00 214.03 ATOM 4291 CB THR E 293 37.215 −74.011 −0.490 1.00 221.76 ATOM 4292 OG1 THR E 293 37.439 −72.739 −1.109 1.00 217.80 ATOM 4293 CG2 THR E 293 38.534 −74.711 −0.156 1.00 225.39 ATOM 4294 N MET E 294 37.655 −75.837 −3.055 1.00 214.96 ATOM 4295 CA MET E 294 38.078 −76.899 −3.914 1.00 216.78 ATOM 4296 C MET E 294 39.265 −77.742 −3.480 1.00 228.86 ATOM 4297 O MET E 294 40.423 −77.285 −3.527 1.00 230.42 ATOM 4298 CB MET E 294 38.253 −76.356 −5.322 1.00 216.89 ATOM 4299 CG MET E 294 38.077 −77.403 −6.379 1.00 220.00 ATOM 4300 SD MET E 294 39.633 −78.117 −6.943 1.00 228.32 ATOM 4301 CE MET E 294 40.351 −76.741 −7.795 1.00 224.44 ATOM 4302 N ASN E 295 38.951 −79.013 −3.095 1.00 229.33 ATOM 4303 CA ASN E 295 39.923 −80.081 −2.812 1.00 233.73 ATOM 4304 C ASN E 295 40.658 −80.256 −4.133 1.00 238.00 ATOM 4305 O ASN E 295 40.037 −80.467 −5.184 1.00 235.69 ATOM 4306 CB ASN E 295 39.237 −81.384 −2.402 1.00 235.01 ATOM 4307 CG ASN E 295 40.201 −82.395 −1.797 1.00 255.03 ATOM 4308 OD1 ASN E 295 40.748 −82.218 −0.695 1.00 248.32 ATOM 4309 ND2 ASN E 295 40.430 −83.483 −2.508 1.00 246.60 ATOM 4310 N SER E 296 41.975 −80.078 −4.077 1.00 236.65 ATOM 4311 CA SER E 296 42.835 −79.925 −5.236 1.00 236.02 ATOM 4312 C SER E 296 43.133 −81.164 −6.067 1.00 238.24 ATOM 4313 O SER E 296 43.296 −81.062 −7.290 1.00 236.25 ATOM 4314 CB SER E 296 44.110 −79.185 −4.837 1.00 242.87 ATOM 4315 OG SER E 296 43.798 −77.991 −4.134 1.00 249.02 ATOM 4316 N SER E 297 43.196 −82.326 −5.409 1.00 235.00 ATOM 4317 CA SER E 297 43.590 −83.584 −6.036 1.00 235.87 ATOM 4318 C SER E 297 42.527 −84.274 −6.879 1.00 232.12 ATOM 4319 O SER E 297 42.835 −85.250 −7.572 1.00 233.97 ATOM 4320 CB SER E 297 44.157 −84.540 −4.986 1.00 244.75 ATOM 4321 OG SER E 297 45.430 −84.124 −4.511 1.00 255.53 ATOM 4322 N ASN E 298 41.288 −83.782 −6.835 1.00 219.93 ATOM 4323 CA ASN E 298 40.180 −84.439 −7.516 1.00 215.01 ATOM 4324 C ASN E 298 39.086 −83.479 −7.942 1.00 210.76 ATOM 4325 O ASN E 298 37.946 −83.900 −8.138 1.00 207.74 ATOM 4326 CB ASN E 298 39.601 −85.484 −6.573 1.00 214.94 ATOM 4327 CG ASN E 298 39.090 −84.892 −5.280 1.00 232.71 ATOM 4328 OD1 ASN E 298 39.452 −83.777 −4.882 1.00 219.13 ATOM 4329 ND2 ASN E 298 38.207 −85.612 −4.613 1.00 230.17 ATOM 4330 N LEU E 299 39.411 −82.183 −8.030 1.00 204.53 ATOM 4331 CA LEU E 299 38.508 −81.110 −8.470 1.00 199.54 ATOM 4332 C LEU E 299 37.179 −81.013 −7.751 1.00 198.32 ATOM 4333 O LEU E 299 36.277 −80.327 −8.215 1.00 195.06 ATOM 4334 CB LEU E 299 38.237 −81.265 −9.966 1.00 198.11 ATOM 4335 CG LEU E 299 39.439 −81.418 −10.837 1.00 206.60 ATOM 4336 CD1 LEU E 299 39.035 −81.605 −12.240 1.00 205.07 ATOM 4337 CD2 LEU E 299 40.342 −80.220 −10.716 1.00 212.90 ATOM 4338 N LEU E 300 37.043 −81.677 −6.628 1.00 194.39 ATOM 4339 CA LEU E 300 35.761 −81.773 −5.966 1.00 191.51 ATOM 4340 C LEU E 300 35.534 −80.702 −4.933 1.00 195.80 ATOM 4341 O LEU E 300 36.339 −80.524 −4.010 1.00 198.92 ATOM 4342 CB LEU E 300 35.693 −83.156 −5.311 1.00 194.03 ATOM 4343 CG LEU E 300 34.398 −83.946 −5.293 1.00 195.93 ATOM 4344 CD1 LEU E 300 34.475 −85.088 −6.308 1.00 196.73 ATOM 4345 CD2 LEU E 300 34.219 −84.587 −3.942 1.00 199.61 ATOM 4346 N CYS E 301 34.403 −80.018 −5.049 1.00 189.73 ATOM 4347 CA CYS E 301 34.022 −79.049 −4.034 1.00 190.92 ATOM 4348 C CYS E 301 33.695 −79.784 −2.736 1.00 196.75 ATOM 4349 O CYS E 301 32.854 −80.684 −2.747 1.00 196.15 ATOM 4350 CB CYS E 301 32.831 −78.228 −4.499 1.00 189.17 ATOM 4351 SG CYS E 301 33.210 −77.054 −5.812 1.00 191.97 ATOM 4352 N THR E 302 34.374 −79.412 −1.638 1.00 195.57 ATOM 4353 CA THR E 302 34.148 −79.928 −0.285 1.00 198.15 ATOM 4354 C THR E 302 33.762 −78.747 0.606 1.00 203.83 ATOM 4355 O THR E 302 34.246 −77.636 0.406 1.00 202.44 ATOM 4356 CB THR E 302 35.387 −80.610 0.269 1.00 205.07 ATOM 4357 OG1 THR E 302 36.446 −79.664 0.287 1.00 201.25 ATOM 4358 CG2 THR E 302 35.801 −81.816 −0.543 1.00 203.88 ATOM 4359 N PRO E 303 32.903 −78.958 1.602 1.00 204.10 ATOM 4360 CA PRO E 303 32.479 −77.842 2.454 1.00 206.12 ATOM 4361 C PRO E 303 33.569 −77.344 3.369 1.00 218.64 ATOM 4362 O PRO E 303 34.543 −78.048 3.594 1.00 219.97 ATOM 4363 CB PRO E 303 31.322 −78.429 3.238 1.00 208.87 ATOM 4364 CG PRO E 303 31.643 −79.871 3.325 1.00 214.74 ATOM 4365 CD PRO E 303 32.247 −80.213 1.999 1.00 207.45 ATOM 4366 N CYS E 304 33.387 −76.148 3.912 1.00 222.04 ATOM 4367 CA CYS E 304 34.388 −75.520 4.747 1.00 228.93 ATOM 4368 C CYS E 304 34.337 −75.876 6.210 1.00 237.79 ATOM 4369 O CYS E 304 33.281 −75.776 6.827 1.00 237.52 ATOM 4370 CB CYS E 304 34.375 −74.010 4.546 1.00 230.31 ATOM 4371 SG CYS E 304 34.621 −73.503 2.833 1.00 231.42 ATOM 4372 N LEU E 305 35.502 −76.261 6.778 1.00 239.18 ATOM 4373 CA LEU E 305 35.682 −76.438 8.220 1.00 244.47 ATOM 4374 C LEU E 305 35.892 −74.976 8.675 1.00 250.42 ATOM 4375 O LEU E 305 36.947 −74.380 8.407 1.00 250.65 ATOM 4376 CB LEU E 305 36.916 −77.319 8.567 1.00 244.41 ATOM 4377 CG LEU E 305 37.176 −77.597 10.081 1.00 248.03 ATOM 4378 CD1 LEU E 305 37.743 −78.988 10.318 1.00 247.74 ATOM 4379 CD2 LEU E 305 38.113 −76.568 10.698 1.00 249.45 ATOM 4380 N GLY E 306 34.857 −74.403 9.292 1.00 249.91 ATOM 4381 CA GLY E 306 34.845 −73.004 9.706 1.00 250.65 ATOM 4382 C GLY E 306 34.681 −72.105 8.494 1.00 253.43 ATOM 4383 O GLY E 306 34.275 −72.601 7.430 1.00 249.28 ATOM 4384 N PRO E 307 35.019 −70.782 8.607 1.00 250.35 ATOM 4385 CA PRO E 307 34.885 −69.888 7.436 1.00 245.14 ATOM 4386 C PRO E 307 35.699 −70.349 6.234 1.00 244.34 ATOM 4387 O PRO E 307 36.746 −70.987 6.390 1.00 245.81 ATOM 4388 CB PRO E 307 35.378 −68.527 7.954 1.00 249.48 ATOM 4389 CG PRO E 307 35.309 −68.605 9.437 1.00 255.48 ATOM 4390 CD PRO E 307 35.527 −70.048 9.793 1.00 252.58 ATOM 4391 N CYS E 308 35.198 −70.042 5.035 1.00 235.87 ATOM 4392 CA CYS E 308 35.881 −70.399 3.794 1.00 233.11 ATOM 4393 C CYS E 308 37.032 −69.450 3.518 1.00 239.94 ATOM 4394 O CYS E 308 36.899 −68.242 3.743 1.00 240.32 ATOM 4395 CB CYS E 308 34.921 −70.406 2.609 1.00 227.97 ATOM 4396 SG CYS E 308 33.659 −71.705 2.660 1.00 229.62 ATOM 4397 N PRO E 309 38.126 −69.944 2.917 1.00 238.09 ATOM 4398 CA PRO E 309 39.201 −69.017 2.534 1.00 239.39 ATOM 4399 C PRO E 309 38.764 −68.208 1.310 1.00 239.61 ATOM 4400 O PRO E 309 38.110 −68.768 0.416 1.00 236.35 ATOM 4401 CB PRO E 309 40.383 −69.941 2.207 1.00 242.88 ATOM 4402 CG PRO E 309 39.931 −71.356 2.565 1.00 247.46 ATOM 4403 CD PRO E 309 38.436 −71.337 2.534 1.00 239.63 ATOM 4404 N LYS E 310 39.054 −66.892 1.300 1.00 236.04 ATOM 4405 CA LYS E 310 38.762 −66.027 0.145 1.00 237.75 ATOM 4406 C LYS E 310 39.630 −64.787 0.090 1.00 255.34 ATOM 4407 O LYS E 310 39.883 −64.282 −1.007 1.00 202.82 ATOM 4408 CB LYS E 310 37.258 −65.708 −0.086 1.00 235.92 ATOM 4409 CG LYS E 310 36.655 −66.350 −1.361 1.00 225.27 ATOM 4410 CD LYS E 310 36.786 −65.512 −2.634 1.00 218.67 ATOM 4411 CE LYS E 310 36.614 −66.371 −3.857 1.00 211.31 ATOM 4412 NZ LYS E 310 36.952 −65.619 −5.088 1.00 211.82 ATOM 4545 N PHE F 705 19.900 −49.424 −19.209 1.00 185.33 ATOM 4546 CA PHE F 705 20.275 −50.514 −20.103 1.00 185.17 ATOM 4547 C PHE F 705 21.295 −50.100 −21.117 1.00 193.52 ATOM 4548 O PHE F 705 22.257 −50.831 −21.309 1.00 194.56 ATOM 4549 CB PHE F 705 19.075 −51.099 −20.827 1.00 186.00 ATOM 4550 CG PHE F 705 19.446 −52.181 −21.814 1.00 186.21 ATOM 4551 CD2 PHE F 705 19.444 −51.930 −23.178 1.00 187.56 ATOM 4552 CD1 PHE F 705 19.825 −53.443 −21.375 1.00 188.11 ATOM 4553 CE2 PHE F 705 19.776 −52.932 −24.088 1.00 189.94 ATOM 4554 CE1 PHE F 705 20.160 −54.442 −22.285 1.00 188.66 ATOM 4555 CZ PHE F 705 20.122 −54.183 −23.636 1.00 187.83 ATOM 4556 N GLU F 706 21.063 −48.993 −21.844 1.00 191.84 ATOM 4557 CA GLU F 706 22.067 −48.476 −22.784 1.00 192.58 ATOM 4558 C GLU F 706 23.339 −48.321 −21.923 1.00 196.89 ATOM 4559 O GLU F 706 24.394 −48.869 −22.259 1.00 195.15 ATOM 4560 CB GLU F 706 21.595 −47.117 −23.360 1.00 194.19 ATOM 4561 CG GLU F 706 22.679 −46.223 −23.953 1.00 203.83 ATOM 4562 CD GLU F 706 22.396 −45.707 −25.350 1.00 220.71 ATOM 4563 OE1 GLU F 706 23.044 −46.201 −26.303 1.00 212.69 ATOM 4564 OE2 GLU F 706 21.523 −44.819 −25.496 1.00 210.82 ATOM 4565 N ASP F 707 23.146 −47.687 −20.732 1.00 195.23 ATOM 4566 CA ASP F 707 24.094 −47.455 −19.637 1.00 195.93 ATOM 4567 C ASP F 707 24.726 −48.781 −19.142 1.00 199.86 ATOM 4568 O ASP F 707 25.843 −48.770 −18.609 1.00 200.04 ATOM 4569 CB ASP F 707 23.422 −46.676 −18.471 1.00 198.28 ATOM 4570 CG ASP F 707 21.896 −46.628 −18.508 1.00 212.14 ATOM 4571 OD1 ASP F 707 21.348 −45.809 −19.282 1.00 213.03 ATOM 4572 OD2 ASP F 707 21.249 −47.421 −17.766 1.00 217.74 ATOM 4573 N TYR F 708 24.007 −49.916 −19.313 1.00 194.77 ATOM 4574 CA TYR F 708 24.530 −51.234 −18.976 1.00 193.75 ATOM 4575 C TYR F 708 25.375 −51.624 −20.181 1.00 192.06 ATOM 4576 O TYR F 708 26.595 −51.672 −20.059 1.00 191.67 ATOM 4577 CB TYR F 708 23.384 −52.238 −18.714 1.00 196.38 ATOM 4578 CG TYR F 708 23.785 −53.697 −18.550 1.00 200.12 ATOM 4579 CD2 TYR F 708 23.982 −54.251 −17.287 1.00 201.14 ATOM 4580 CD1 TYR F 708 23.825 −54.558 −19.646 1.00 202.45 ATOM 4581 CE2 TYR F 708 24.249 −55.613 −17.121 1.00 201.97 ATOM 4582 CE1 TYR F 708 24.139 −55.911 −19.495 1.00 203.66 ATOM 4583 CZ TYR F 708 24.332 −56.440 −18.228 1.00 209.05 ATOM 4584 OH TYR F 708 24.597 −57.783 −18.067 1.00 209.27 ATOM 4585 N LEU F 709 24.729 −51.780 −21.361 1.00 184.40 ATOM 4586 CA LEU F 709 25.309 −52.165 −22.642 1.00 182.32 ATOM 4587 C LEU F 709 26.686 −51.583 −22.902 1.00 184.12 ATOM 4588 O LEU F 709 27.588 −52.316 −23.284 1.00 182.43 ATOM 4589 CB LEU F 709 24.363 −51.826 −23.784 1.00 181.94 ATOM 4590 CG LEU F 709 24.516 −52.751 −24.968 1.00 186.75 ATOM 4591 CD1 LEU F 709 23.177 −53.192 −25.479 1.00 187.35 ATOM 4592 CD2 LEU F 709 25.339 −52.120 −26.071 1.00 189.52 ATOM 4593 N HIS F 710 26.844 −50.271 −22.675 1.00 179.97 ATOM 4594 CA HIS F 710 28.108 −49.569 −22.855 1.00 178.88 ATOM 4595 C HIS F 710 29.151 −50.089 −21.879 1.00 179.18 ATOM 4596 O HIS F 710 30.145 −50.663 −22.314 1.00 178.29 ATOM 4597 CB HIS F 710 27.929 −48.047 −22.692 1.00 179.80 ATOM 4598 CG HIS F 710 27.077 −47.378 −23.729 1.00 183.06 ATOM 4599 ND1 HIS F 710 26.729 −48.015 −24.915 1.00 184.75 ATOM 4600 CD2 HIS F 710 26.573 −46.122 −23.741 1.00 184.44 ATOM 4601 CE1 HIS F 710 25.996 −47.143 −25.582 1.00 184.10 ATOM 4602 NE2 HIS F 710 25.887 −45.985 −24.920 1.00 184.35 ATOM 4603 N ASN F 711 28.897 −49.943 −20.567 1.00 173.66 ATOM 4604 CA ASN F 711 29.771 −50.419 −19.498 1.00 173.15 ATOM 4605 C ASN F 711 30.283 −51.872 −19.699 1.00 176.40 ATOM 4606 O ASN F 711 31.379 −52.185 −19.246 1.00 176.64 ATOM 4607 CB ASN F 711 29.073 −50.271 −18.143 1.00 175.14 ATOM 4608 CG ASN F 711 29.275 −48.940 −17.447 1.00 198.08 ATOM 4609 OD1 ASN F 711 30.290 −48.259 −17.635 1.00 193.99 ATOM 4610 ND2 ASN F 711 28.307 −48.537 −16.614 1.00 185.99 ATOM 4611 O VAL F 712 31.806 −54.707 −22.029 1.00 169.94 ATOM 4612 N VAL F 712 29.501 −52.747 −20.384 1.00 171.53 ATOM 4613 CA VAL F 712 29.884 −54.143 −20.695 1.00 170.19 ATOM 4614 C VAL F 712 30.676 −54.213 −22.002 1.00 172.12 ATOM 4615 CB VAL F 712 28.708 −55.183 −20.661 1.00 173.30 ATOM 4616 CG1 VAL F 712 27.351 −54.532 −20.818 1.00 172.82 ATOM 4617 CG2 VAL F 712 28.890 −56.304 −21.688 1.00 172.86 ATOM 4618 O VAL F 713 32.557 −53.252 −25.667 1.00 169.23 ATOM 4619 N VAL F 713 30.043 −53.717 −23.078 1.00 168.79 ATOM 4620 CA VAL F 713 30.492 −53.669 −24.469 1.00 167.59 ATOM 4621 C VAL F 713 31.855 −52.928 −24.704 1.00 170.88 ATOM 4622 CB VAL F 713 29.285 −53.114 −25.275 1.00 170.11 ATOM 4623 CG1 VAL F 713 29.682 −52.312 −26.495 1.00 170.05 ATOM 4624 CG2 VAL F 713 28.310 −54.221 −25.627 1.00 169.52 ATOM 4625 O PHE F 714 35.718 −51.468 −23.045 1.00 156.77 ATOM 4626 N PHE F 714 32.239 −51.984 −23.790 1.00 167.63 ATOM 4627 CA PHE F 714 33.424 −51.114 −23.898 1.00 175.55 ATOM 4628 C PHE F 714 34.510 −51.293 −22.777 1.00 194.14 ATOM 4629 CB PHE F 714 32.947 −49.624 −24.032 1.00 176.93 ATOM 4630 CG PHE F 714 32.043 −49.243 −25.217 1.00 177.36 ATOM 4631 CD1 PHE F 714 32.554 −49.151 −26.511 1.00 178.99 ATOM 4632 CD2 PHE F 714 30.705 −48.921 −25.022 1.00 178.41 ATOM 4633 CE1 PHE F 714 31.726 −48.817 −27.589 1.00 178.89 ATOM 4634 CE2 PHE F 714 29.880 −48.582 −26.105 1.00 180.35 ATOM 4635 CZ PHE F 714 30.399 −48.524 −27.377 1.00 177.82 END Note: The coordinates in this Appendix describe the asymmetric unit of the crystal unit cell. 

1. (canceled)
 2. (canceled)
 3. A method of identifying, designing or screening for a compound that can potentially mimic insulin interacting with IR, including performing structure-based identification, design, or screening of a compound based on (i) the compound's interactions with an IR structure and/or (ii) the compound's similarity with an insulin structure in complex with an IR defined by the atomic coordinates shown in Appendix I or a subset thereof.
 4. A method for identifying an agonist or antagonist compound comprising an entity selected from the group consisting of an antibody, a peptide, a non-peptide molecule and a chemical compound, wherein said compound is capable of enhancing, eliciting or blocking biological activity resulting from an interaction with insulin and/or the IR, wherein said process includes: introducing into a suitable computer program parameters defining an interacting surface based on the conformation of insulin and/or IR corresponding to the atomic coordinates of Appendix I or a subset thereof, wherein said program displays a three-dimensional model of the interacting surface; creating a three-dimensional structure of a test compound in said computer program; displaying a superimposing model of said test compound on the three-dimensional model of the interacting surface; assessing whether said test compound model fits spatially into a binding site; optionally incorporating said test compound in a biological activity assay; and optionally determining whether said test compound inhibits or enhances the biological activity of insulin or IR signalling or signalling by a derivative of insulin or IR.
 5. (canceled)
 6. (canceled)
 7. (canceled)
 8. (canceled)
 9. (canceled)
 10. (canceled)
 11. (canceled)
 12. (canceled)
 13. An agonist or antagonist of a site comprising one or more amino acids selected from 1 to 310 and 704 to 719 of the IR α-chain including one or more amino acids selected from the group consisting of Asp 12, Arg14, Leu36, Leu37, Phe39, Lys40, Leu62, Phe64, Arg65, Phe88, Phe89, Tyr91, Val94, Phe96, Arg118, Glu120, His144, Phe705, Tyr708, Leu709, His710, Asn711, Val712, Val713, Phe714 and Val715.
 14. An agonist or antagonist that can potentially mimic insulin interacting with IR, said agonist or antagonist comprising one or more amino acids selected from 1 to 30 from the insulin B-chain including one or more amino acids selected from the group consisting of Gly8, Ser9, Leu11, Val12, Leu15, Tyr16, Phe24, Phe25 and Tyr26, or one or more amino acids selected from the insulin A-chain including one or more amino acids selected from the group consisting of Gly1, Ile2, Val3, Glu4 and Tyr19.
 15. (canceled)
 16. A method of redesigning a compound which is known to bind to IR and/or IGF-1R comprising performing structure-based evaluation of the compound based on the compound's interactions with an IR structure defined by the atomic coordinates of Appendix I or a subset thereof and redesigning or chemically modifying the compound as a result of the evaluation, or the compound's similarity with an insulin structure in complex with an IR defined by the atomic coordinates of Appendix I or a subset thereof and redesigning or chemically modifying the compound as a result of the evaluation.
 17. (canceled)
 18. (canceled)
 19. (canceled)
 20. A computer-assisted method of identifying a compound that potentially interacts with IR and/or IGF-1R, which method comprises fitting the structure of: (i) the Site 1 binding site of IR, the structure being defined by a subset of the atomic coordinates shown in Appendix I; and/or (ii) portions of the N- and C-terminal regions of the IR α-chain, which are in complex with insulin, the structure being defined by a subset of the atomic coordinates shown in Appendix I, to the structure of a candidate compound.
 21. A computer-assisted method for identifying a molecule able to interact with IR and/or IGF-1R using a programmed computer comprising a processor, which method comprises the steps of: (a) generating, using computer methods, a set of atomic coordinates of a structure that possesses energetically favourable interactions with the atomic coordinates of: (i) the Site 1 binding site of IR, the structure being defined by a subset of the atomic coordinates shown in Appendix I; and/or (ii) portions of the N- and C-terminal regions of the IR α-chain, which are in complex with insulin, the structure being defined by a subset of the atomic coordinates shown in Appendix I, which coordinates are entered into the computer thereby generating a criteria data set; (b) comparing, using the processor, the criteria data set to a computer database of chemical structures; (c) selecting from the database, using computer methods, chemical structures which are complementary or similar to a region of the criteria data set; and (d) optionally outputting, to an output device, the selected chemical structures which are complementary to or similar to a region of the criteria data set.
 22. A computer-assisted method for identifying potential mimetics of IR, insulin and/or IGF-1R using a programmed computer comprising a processor, the method comprising the steps of: (a) generating a criteria data set from a set of atomic coordinates of: (i) the Site 1 binding site of IR, the structure being defined by a subset of the atomic coordinates shown in Appendix I; (ii) portions of the N- and C-terminal regions of the IR α-chain, which are in complex with insulin, the structure being defined by a subset of the atomic coordinates shown in Appendix I; (iii) insulin, the structure being defined by a subset of the atomic coordinates shown in Appendix I; and/or (iv) the Site 1 binding site of insulin or portions thereof, the structure being defined by a subset of the atomic coordinates shown in Appendix I, which coordinates are entered into the computer; (b): (i) comparing, using the processor, the criteria data set to a computer database of chemical structures stored in a computer data storage system and selecting from the database, using computer methods, chemical structures having a region that is structurally similar to the criteria data set; or (ii) constructing, using computer methods, a model of a chemical structure having a region that is structurally similar to the criteria data set; and, optionally, (c) optionally outputting to an output device: (i) the selected chemical structures from step (b)(i) having a region similar to the criteria data set; or (ii) the constructed model from step (b)(ii).
 23. A method for evaluating the ability of a compound to interact with IR and/or IGF-1R, the method comprising the steps of: (a) employing computational means to perform: (i) a fitting operation between the compound and the binding surface of a computer model of the Site 1 binding site for insulin on IR; and/or (ii) a superimposing operation between the compound and insulin, the Site 1 binding site of insulin, or a portion thereof, using atomic coordinates wherein the root mean square deviation between the atomic coordinates and a subset of atomic coordinates of Appendix I or a subset of atomic coordinates of one or more thereof at least representing the N-terminal region of the IR α-chain, the C-terminal region of IR α-chain, insulin, the Site 1 binding site of insulin, or a portion of the Site 1 binding site of insulin, is not more than 1.5 Å; and (b) analysing the results of the fitting operation and/or superimposing operation to quantify the association between the compound and the binding surface model.
 24. A method of using molecular replacement to obtain structural information about a molecule or a molecular complex of an unknown structure, comprising the steps of: (i) generating an X-ray diffraction pattern of the crystallized molecule or molecular complex; and (ii) applying the atomic coordinates of Appendix I, or a subset of atomic coordinates thereof at least representing the N-terminal region of the IR α-chain, the C-terminal region of IR α-chain, insulin, mimetics thereof, derivatives thereof, or portions thereof, to the X-ray diffraction pattern to generate a three-dimensional electron density map of at least a region of the molecule or molecular complex whose structure is unknown. 